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Zehra Z, von Bartheld CS, Khan W, Azam M, Qamar R. Prevalence of strabismus in Pakistan: a systematic review and meta-analysis. Strabismus 2025; 33:44-53. [PMID: 39351897 PMCID: PMC11821445 DOI: 10.1080/09273972.2024.2408416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/03/2024]
Abstract
Purpose: Strabismus is an ocular condition characterized by misalignment of the visual axis. The global prevalence of strabismus is about 2-3%, which varies between different countries and ethnicities. The aim of this study was to conduct a meta-analysis of studies, which had previously reported the prevalence of strabismus in Pakistan, in order to obtain the overall prevalence of strabismus in the country. Methods: All community-based studies reporting the prevalence of strabismus from Pakistan were searched using international databases and local ophthalmology journals. Information about sample size, number of individuals with strabismus, and location and duration of the study was recorded. Statistical analysis including heterogeneity testing, pooled prevalence calculation and regression analysis were done using the R software. Results: Heterogeneity tests, Pheterogeneity < .01, suggested high heterogeneity between the different studies. The pooled prevalence of strabismus was 0.7% [95% confidence interval (CI): 0.39%-1.23%] according to the random effects model, with a decreasing trend in prevalence from 1995 to 2020. Esotropia was more frequent than exotropia in both population-based and clinic-based studies. Conclusion: The prevalence of strabismus in Pakistan is comparatively lower than the worldwide prevalence, and it appears to be decreasing over the last three decades, consistent with global trends.
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Affiliation(s)
- Zainab Zehra
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
| | | | - Wishal Khan
- Department of Molecular Biology, Virtual University of Pakistan, Pakistan
| | - Maleeha Azam
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
| | - Raheel Qamar
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
- Pakistan Academy of Sciences, Islamabad, Pakistan
- Science and Technology Sector, ICESCO, Rabat, Kingdom of Morocco
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Matsuo T, Hamasaki I, Kamatani Y, Kawaguchi T, Yamaguchi I, Matsuda F, Saito A, Nakazono K, Kamitsuji S. Genome-Wide Association Study with Three Control Cohorts of Japanese Patients with Esotropia and Exotropia of Comitant Strabismus and Idiopathic Superior Oblique Muscle Palsy. Int J Mol Sci 2024; 25:6986. [PMID: 39000095 PMCID: PMC11241339 DOI: 10.3390/ijms25136986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 06/10/2024] [Accepted: 06/15/2024] [Indexed: 07/16/2024] Open
Abstract
Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F, respectively, as candidate genes at a significant level of p < 5 × 10-8, while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10-6. In comparison with BBJ (180K), RARB (retinoic acid receptor-β) was detected as a candidate at a significant level of p < 5 × 10-8 in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus.
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Affiliation(s)
- Toshihiko Matsuo
- Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama City 700-8558, Japan
- Department of Ophthalmology, Okayama University Hospital, Okayama City 700-8558, Japan
| | - Ichiro Hamasaki
- Department of Ophthalmology, Okayama University Hospital, Okayama City 700-8558, Japan
| | - Yoichiro Kamatani
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan;
| | - Takahisa Kawaguchi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (F.M.)
| | - Izumi Yamaguchi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (F.M.)
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (F.M.)
| | - Akira Saito
- StaGen Co., Ltd., Tokyo 111-0051, Japan (S.K.)
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Abstract
Strabismus, or misalignment of the eyes, is the most common ocular disorder in the pediatric population, affecting approximately 2%-4% of children. Strabismus leads to the disruption of binocular vision, amblyopia, social and occupational discrimination, and decreased quality of life. Although it has been recognized since ancient times that strabismus runs in families, its inheritance patterns are complex, and its precise genetic mechanisms have not yet been defined. Family, population, and twin studies all support a role of genetics in the development of strabismus. There are multiple forms of strabismus, and it is not known if they have shared genetic mechanisms or are distinct genetic disorders, which complicates studies of strabismus. Studies assuming that strabismus is a Mendelian disorder have found areas of linkage and candidate genes in particular families, but no definitive causal genes. Genome-wide association studies searching for common variation that contributes to strabismus risk have identified two risk loci and three copy number variants in white populations. Causative genes have been identified in congenital cranial dysinnervation disorders, syndromes in which eye movement is limited or paralyzed. The causative genes lead to either improper differentiation of cranial motor neurons or abnormal axon guidance. This article reviews the evidence for a genetic contribution to strabismus and the recent advances that have been made in the genetics of comitant strabismus, the most common form of strabismus.
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Affiliation(s)
- Mayra Martinez Sanchez
- Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Mary C. Whitman
- Department of Ophthalmology, Boston Children’s Hospital, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
- F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, United States
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Zehra Z, Khan N, Nadeem M, Siddiqui SN, von Bartheld CS, Azam M, Qamar R. Association of IGF1 polymorphisms with exotropia in a Pakistani cohort. Mol Vis 2022; 28:369-377. [PMID: 36338665 PMCID: PMC9603902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 10/04/2022] [Indexed: 06/16/2023] Open
Abstract
PURPOSE Strabismus (STBMS) is a multifactorial ocular disorder in children that leads to misalignment of the eyes. Insulin-like growth factor 1 (IGF1) has been shown to be involved in the development of extraocular muscles and myopia; however, data are limited on the genetic associations of IGF1 with STBMS in Pakistan. METHODS Two hundred seventy-four STBMS cases and 272 unaffected controls were recruited, and their DNA was extracted. Two IGF1 single nucleotide polymorphisms, rs6214 and rs5742632, were genotyped using PCR-restriction fragment length polymorphism. Univariate logistic regression analysis was performed to determine the association of these single nucleotide polymorphisms with STBMS, and the results were adjusted for age and sex. In addition, 26 extraocular muscle tissues were collected from patients with STBMS undergoing squint correction surgery, along with 3 deceased control samples. IGF1 mRNA expression was measured by quantitative PCR; the Mann-Whitney U test was applied, and fold change was calculated. Logistic regression analysis was applied to determine the association of RNA expression and fold change with genotype. RESULTS Multivariate logistic regression analysis revealed that rs5742632 (odds ratio [95% confidence interval] = 1.05[1.01-1.06], p = 0.03) is associated with STBM. Moreover, rs6214 (1.03[1.01-1.05], p = 0.03) and rs5742632 (1.09[1.04-1.11], p = 0.04) were associated with exotropia. Statistically, no significant difference in IGF1 mRNA expression in the extraocular muscles between the STBMS cases and the controls was observed. CONCLUSIONS IGF1 polymorphisms rs5742632 (A>G) and rs6214 (C>T) are plausible risk factors for the development of exotropia. However, the physiologic mechanism requires further evaluation.
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Affiliation(s)
- Zainab Zehra
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV
| | - Netasha Khan
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
| | - Minhal Nadeem
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
| | | | | | - Maleeha Azam
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
| | - Raheel Qamar
- Translational Genomics Laboratory, Department of Biosciences, COMSATS University Islamabad, Pakistan
- Pakistan Academy of Sciences, Islamabad, Pakistan
- Science and Technology Sector, ICESCO, Rabat, Morocco
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Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy. Int J Mol Sci 2022; 23:ijms23158626. [PMID: 35955756 PMCID: PMC9369257 DOI: 10.3390/ijms23158626] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/24/2022] [Accepted: 07/31/2022] [Indexed: 02/01/2023] Open
Abstract
Idiopathic superior oblique muscle palsy is a major type of paralytic, non-comitant strabismus and presents vertical and cyclo-torsional deviation of one eye against the other eye, with a large vertical fusion range and abnormal head posture such as head tilt. Genetic background is considered to play a role in its development, as patients with idiopathic superior oblique muscle palsy have varying degrees of muscle hypoplasia and, rarely, the complete absence of the muscle, that is, aplasia. In this study, whole genome sequencing was performed, and single nucleotide variations and short insertions/deletions (SNVs/InDels) were annotated in two patients each in three small families (six patients in total) with idiopathic superior oblique muscle palsy, in addition to three normal individuals in one family. At first, linkage analysis was carried out in the three families and SNVs/InDels in chromosomal loci with negative LOD scores were excluded. Next, SNVs/InDels shared by the six patients, but not by the three normal individuals, were chosen. SNVs/InDels were further narrowed down by choosing low-frequency (<1%) or non-registered SNVs/InDels in four databases for the Japanese population, and then by choosing SNVs/InDels with functional influence, leading to one candidate gene, SSTR5-AS1 in chromosome 16. The six patients were heterozygous for 13-nucleotide deletion in SSTR5-AS1, except for one homozygous patient, while the three normal individuals were wild type. Targeted polymerase chain reaction (PCR) and direct sequencing of PCR products confirmed the 13-nucleotide deletion in SSTR5-AS1. In the face of newly-registered SSTR5-AS1 13-nucleotide deletion at a higher frequency in a latest released database for the Japanese population, the skipping of low-frequency and non-registration sorting still resulted in only 13 candidate genes including SSTR5-AS1 as common variants. The skipping of linkage analysis also led to the same set of 13 candidate genes. Different testing strategies that consisted of linkage analysis and simple unintentional bioinformatics could reach candidate genes in three small families with idiopathic superior oblique muscle palsy.
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Commonly occurring genetic polymorphisms with a major impact on the risk of nonsyndromic strabismus: replication in a sample from Finland. J AAPOS 2022; 26:12.e1-12.e6. [PMID: 34856371 DOI: 10.1016/j.jaapos.2021.07.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 11/20/2022]
Abstract
PURPOSE To replicate associations between polymorphisms in the WRB and TSPAN10 genes and strabismus in an independent Finnish cohort and to calculate their population attributable risk. METHODS Polymorphisms in the WRB (rs2244352) and TSPAN10 (rs6420484) genes were investigated in individuals from the FinnGen study group who had one of three categories of strabismus, with clinical diagnoses of (1) "strabismus-all subtypes" (3,515 cases and 173,384 controls), (2) "convergent concomitant strabismus" (ICD-10 code H50.0; 737 cases and 170,976 controls), and (3) "divergent concomitant strabismus" (ICD-10 code H50.1; 1,059 cases and 170,976 controls). RESULTS The WRB polymorphism was associated with "all subtypes" of strabismus (OR = 1.08; P = 0.008) and divergent strabismus (OR = 1.11; P = 0.046) but not with convergent strabismus (P = 0.41). The WRB polymorphism had a population attributable risk of 3.4% for all strabismus subtypes and 4.7% for divergent strabismus. The TSPAN10 polymorphism was associated with all three strabismus phenotypes: "all subtypes" (OR = 1.08; P = 0.002), convergent strabismus (OR = 1.19; P = 0.001) and divergent strabismus (OR = 1.20; P =7.21E-05). The population attributable risk for the TSPAN10 polymorphism was 6.0% for any strabismus, 13.3% for convergent strabismus, and 13.9% for divergent strabismus. CONCLUSIONS Genetic association with strabismus was replicated in a Finnish cohort for two common polymorphisms. Under the assumption that these polymorphisms are independent of other risk factors, they are responsible for up to 20% of isolated cases of strabismus in Finland, similar to estimates in other European populations.
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Whole Exome-Sequencing of Pooled Genomic DNA Samples to Detect Quantitative Trait Loci in Esotropia and Exotropia of Strabismus in Japanese. LIFE (BASEL, SWITZERLAND) 2021; 12:life12010041. [PMID: 35054434 PMCID: PMC8777842 DOI: 10.3390/life12010041] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/30/2021] [Accepted: 12/23/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Esotropia and exotropia are two major phenotypes of comitant strabismus. It remains controversial whether esotropia and exotropia would share common genetic backgrounds. In this study, we used a quantitative trait locus (QTL)-sequencing pipeline for diploid plants to screen for susceptibility loci of strabismus in whole exome sequencing of pooled genomic DNAs of individuals. METHODS Pooled genomic DNA (2.5 ng each) of 20 individuals in three groups, Japanese patients with esotropia and exotropia, and normal members in the families, was sequenced twice after exome capture, and the first and second sets of data in each group were combined to increase the read depth. The SNP index, as the ratio of variant genotype reads to all reads, and Δ(SNP index) values, as the difference of SNP index between two groups, were calculated by sliding window analysis with a 4 Mb window size and 10 kb slide size. The rows of 200 "N"s were inserted as a putative 200-b spacer between every adjoining locus to depict Δ(SNP index) plots on each chromosome. SNP positions with depth < 20 as well as SNP positions with SNP index of <0.3 were excluded. RESULTS After the exclusion of SNPs, 12,242 SNPs in esotropia/normal group and 12,108 SNPs in exotropia/normal group remained. The patterns of the Δ(SNP index) plots on each chromosome appeared different between esotropia/normal group and exotropia/normal group. When the consecutive groups of SNPs on each chromosome were set at three patterns: SNPs in each cytogenetic band, 50 consecutive sliding SNPs, and SNPs in 4 Mb window size with 10 kb slide size, p values (Wilcoxon signed rank test) and Q values (false discovery rate) in a few loci as Manhattan plots showed significant differences in comparison between the Δ(SNP index) in the esotropia/normal group and exotropia/normal group. CONCLUSIONS The pooled DNA sequencing and QTL mapping approach for plants could provide overview of genetic background on each chromosome and would suggest different genetic backgrounds for two major phenotypes of comitant strabismus, esotropia and exotropia.
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Wang Y, Chen X, Jiang T, Gu Y, Zhang X, Yuan W, Zhao A, Li R, Wang Z, Hu Z, Liu H. Expanding the phenotypic spectrum of mutations in LRP2: a novel candidate gene of non-syndromic familial comitant strabismus. J Transl Med 2021; 19:495. [PMID: 34872573 PMCID: PMC8647414 DOI: 10.1186/s12967-021-03155-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 11/19/2021] [Indexed: 11/29/2022] Open
Abstract
Background Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. Studies have confirmed that genetic factors play an important role in the development of CS. The aim of this study was to identify the genetic cause of non-syndromic familial CS. Methods Fourteen unrelated CS families were recruited for the study. Twelve affected and 2 unaffected individuals from a large four-generation family (CS08) were selected to perform whole genome-wide linkage analysis. Parallel whole-exome sequencing (WES) was conducted in the same family (9 patients and 1 unaffected member) and 31 additional CS cases from 13 other unrelated families. Sanger sequencing was used to determine whether any of the remaining variants co-segregated with the disease phenotype in the corresponding family. Results Based on linkage analysis, CS in family CS08 mapped to a novel region of 34.17 centimorgan (cM) on chromosome 2q22.3-2q32.1 between markers D2S151 and D2S364, with a maximum log odds (LOD) score of 3.54 (theta = 0) at D2S142. Parallel WES identified a heterozygous variant, LRP2 c.335 A > G (p.Q112R), located in such a linkage interval that completely co-segregated with the disease in the family. Furthermore, another novel heterozygous variant (c.7274A > G, p.D2425G) in LRP2 that co-segregated was detected in 2 additional affected individuals from another unrelated family by WES. Both variants are predicted to be damaging by PolyPhen-2, SIFT and MutationTaster, and were absent in 100 ethnically matched normal controls. Conclusion LRP2 is a novel candidate genetic cause of non-syndromic familial CS. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-03155-z.
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Affiliation(s)
- Yue Wang
- Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Rd, NanjingNanjing, 211166, China
| | - Xuejuan Chen
- Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029, China.,Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Rd, NanjingNanjing, 211166, China
| | - Tao Jiang
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Rd, NanjingNanjing, 211166, China
| | - Yayun Gu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Rd, NanjingNanjing, 211166, China
| | - Xiaohan Zhang
- Department of Ophthalmology, Wuxi Children's Hospital, Wuxi, China
| | - Wenwen Yuan
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Andi Zhao
- Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029, China
| | - Rui Li
- Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029, China
| | - Zijin Wang
- Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029, China
| | - Zhibin Hu
- Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. .,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Rd, NanjingNanjing, 211166, China.
| | - Hu Liu
- Department of Ophthalmology, The First Affiliated Hospital With Nanjing Medical University, 300 Guangzhou Rd, Nanjing, 210029, China.
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Shen T, Qiu X, Lin X, Lin J, Li X, Chen Q, Pan L, Wang Z, Shen H, Zhang Q, Yan J. Missense mutation in the PAX6 gene can cause a complex mild variable phenotype predominated by concomitant strabismus. Ophthalmic Genet 2021; 43:88-96. [PMID: 34344282 DOI: 10.1080/13816810.2021.1961283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
PURPOSE We aimed to reveal the underlying genetic defect in a multigenerational Chinese family with autosomal dominant concomitant strabismus complicated by multiple ocular developmental abnormalities. METHODS Comprehensive ophthalmic examinations were performed in 14 patients and 24 healthy family members. Whole exome sequencing was performed, and Sanger sequencing was used to confirm the probable mutation in all the family members. RESULTS Concomitant strabismus was the predominant phenotype in the affected family members, although the patients also exhibited variable phenotypes, including nystagmus, mild iris abnormalities, myopia, cataract, and coloboma. An R208W mutation in PAX6 was identified as the pathogenic mutation in the affected family members. CONCLUSIONS We recommend considering PAX6 as a candidate gene in the diagnostic screen for familial concomitant strabismus in order to avoid missed diagnosis of the mild ocular abnormalities. Careful examinations of mild ocular phenotypes are necessary for an accurate diagnosis of varied ocular abnormalities in the families with the PAX6 mutation, and proper diagnosis can facilitate genetic and clinical counseling for affected patients.
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Affiliation(s)
- Tao Shen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xuan Qiu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiaoming Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jing Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiuling Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Qiwen Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Liuqing Pan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Zhonghao Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Huangxuan Shen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Qingjiong Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jianhua Yan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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Feng YL, Li ND. Duplication of 19q (13.2-13.31) associated with comitant esotropia: A case report. World J Clin Cases 2021; 9:5526-5534. [PMID: 34307605 PMCID: PMC8281424 DOI: 10.12998/wjcc.v9.i20.5526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 12/23/2020] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Comitant esotropia is the most common form of strabismus. It is caused by heterogeneous environmental and genetic risk factors. The pure duplication of the long arm of chromosome 19 is a rare abnormality. Only 8 patients with partial trisomy of the long arm of chromosome 19q have been reported to date. Here, we describe a girl with pure duplication of 19q, who was diagnosed with congenital esotropia, microcephaly, and gallbladder agenesis.
CASE SUMMARY The patient was diagnosed with esotropia when she was 1-year-old. The Krimsky method showed +50 prism diopters in the primary gaze position. No additional abnormal findings were observed following slit lamp and fundus examination, but the features of the full-field electroretinogram showed a decreased amplitude and increased implicit times. Magnetic resonance imaging showed ventriculomegaly with thinning of the corpus callosum and splenium in her brain. A 4.42 Mb mosaic duplication within 19q13.2-q13.31 region (chr19:39,343,725 to 43,762,586) was detected by microarray comparative genomic hybridization.
CONCLUSION Strabismus is reported in many live borns with pure duplication of 19q. This important clinical characteristic indicates that the candidate genes fundamental for this phenotype may be narrowed to genes within the 19q13.3-q13.31 region. There were two candidate genes observed that may contribute to the comitant esotropia phenotype, namely XRCC1 (19:43,543,311) and SMG9 (19:43,727,991).
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Affiliation(s)
- Yue-Lan Feng
- Department of Ophthalmology, National Center for Children's Health, Beijing Children’s Hospital, Capital Medical University, Beijing 100045, China
- Department of Ophthalmology, First Hospital Affiliated to Baotou Medical College, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - Ning-Dong Li
- Department of Ophthalmology, National Center for Children's Health, Beijing Children’s Hospital, Capital Medical University, Beijing 100045, China
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Mohney BG, Lepor L, Hodge DO. Subclinical markers of strabismus in children 5-18 years of age. J AAPOS 2021; 25:139.e1-139.e5. [PMID: 34082112 DOI: 10.1016/j.jaapos.2021.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE To report the prevalence of subclinical markers of strabismus from a community-based screening of children. METHODS A family history and ophthalmic examination (including six markers of strabismus: oblique muscle dysfunction, stereopsis <60 arcsec, monofixation, nasal-temporal pursuit asymmetry, dissociated strabismus, and anisometropia) were obtained from consecutive children, aged 5-18 years, in the local school system and the pediatric outpatient clinic of Mayo Clinic, Rochester, Minnesota. RESULTS A total of 1,000 children (498 males [49.8%]) were examined at a mean age of 10.6 years (range, 5-18.98). Of the 1,000, 57 (5.7%) had strabismus, and 130 (13%) had some form of phoria. Of the 943 children without strabismus, 103 (10.9%) had one or more of the six subclinical markers, including 43 (4.5%) with inferior oblique dysfunction, 37 (3.9%) with anisometropia, 34 (3.6%) with subnormal stereopsis, 6 (0.6%) with nasal-temporal pursuit asymmetry, 3 (0.3%) with monofixation, and none with dissociated strabismus. A subclinical marker of strabismus occurred in 20 (12.7%) of the 157 nontropic subjects who had a family history of either strabismus, amblyopia, or both and in 83 (10.6%) of the 786 nontropic children without a family history. CONCLUSIONS In this community-based screening of children, subclinical disorders of binocular vision occurred in 10%-13% of children without strabismus, of which inferior oblique muscle dysfunction, anisometropia, and subnormal stereopsis were most prevalent. Identifying these disorders among strabismic families may be useful in elucidating the genetic puzzle of childhood strabismus.
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Affiliation(s)
- Brian G Mohney
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota.
| | - Laura Lepor
- Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota
| | - David O Hodge
- Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida
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12
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Identification of Possible Risk Variants of Familial Strabismus Using Exome Sequencing Analysis. Genes (Basel) 2021; 12:genes12010075. [PMID: 33435129 PMCID: PMC7827096 DOI: 10.3390/genes12010075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/31/2020] [Accepted: 01/06/2021] [Indexed: 11/16/2022] Open
Abstract
PURPOSE To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. METHODS Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus and available unaffected family members were evaluated using whole exome sequencing. The primary outcome was to identify rare occurring variants among affected individuals and investigate the evidence of their genetic heterogeneity. These results were compared with exome sequencing analysis to build a comprehensive genetic profile of the study families. RESULTS We observed 60 variants from 58 genes in 53 patients diagnosed with strabismus. We prioritized the most credible risk variants, which showed clear segregation in family members affected by strabismus. As a result, we found risk variants in four genes (FAT3, KCNH2, CELSR1, and TTYH1) in five families, suggesting their role in development of familial strabismus. In other families, there were several rare genetic variants in affected cases, but we did not find clear segregation pattern across family members. CONCLUSION Genomic sequencing holds great promise in elucidating the genetic causes of strabismus; further research with larger cohorts or other related approaches are warranted.
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13
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Whitman MC, Di Gioia SA, Chan WM, Gelber A, Pratt BM, Bell JL, Collins TE, Knowles JA, Armoskus C, Pato M, Pato C, Shaaban S, Staffieri S, MacKinnon S, Maconachie GDE, Elder JE, Traboulsi EI, Gottlob I, Mackey DA, Hunter DG, Engle EC. Recurrent Rare Copy Number Variants Increase Risk for Esotropia. Invest Ophthalmol Vis Sci 2021; 61:22. [PMID: 32780866 PMCID: PMC7443120 DOI: 10.1167/iovs.61.10.22] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia. Methods CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints. Results Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 × 10−6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95% confidence interval [CI] 5.4–38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95% CI 4.6–25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95% CI 5.4–14.9). Overall, 114 cases (7%) and only 28 controls (0.7%) had one of the three rare duplications. No case nor control had more than one of these three duplications. Conclusions Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.
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Affiliation(s)
- Mary C Whitman
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.,F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Silvio Alessandro Di Gioia
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Wai-Man Chan
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Alon Gelber
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Brandon M Pratt
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Jessica L Bell
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.,F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Thomas E Collins
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
| | - James A Knowles
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, New York, United States
| | - Christopher Armoskus
- Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, New York, United States
| | - Michele Pato
- Institute for Genomic Health, SUNY Downstate Medical Center, Brooklyn, New York, United States
| | - Carlos Pato
- Institute for Genomic Health, SUNY Downstate Medical Center, Brooklyn, New York, United States
| | - Sherin Shaaban
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States.,Present address: Department of Pathology and ARUP Laboratories, University of Utah School of Medicine, Salt Lake City, Utah, United States
| | - Sandra Staffieri
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
| | - Sarah MacKinnon
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Gail D E Maconachie
- Department of Neuroscience, Psychology and Behavior, The University of Leicester Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom
| | - James E Elder
- Department of Ophthalmology, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.,Department of Pediatrics, The University of Melbourne, Parkville, Victoria, Australia
| | - Elias I Traboulsi
- Department of Pediatric Ophthalmology and Strabismus, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - Irene Gottlob
- Department of Neuroscience, Psychology and Behavior, The University of Leicester Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom
| | - David A Mackey
- Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.,Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.,Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia
| | - David G Hunter
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Elizabeth C Engle
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.,F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States.,Howard Hughes Medical Institute, Chevy Chase, Maryland, United States
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14
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Chen D, Li R, Li X, Huang D, Wang Y, Zhao X, Zhang X, Sun Q, Hao Q, Tong H, Yao X, Fan W, Lu W, Dang J, Zhu H, Liu H. Prevalence, incidence and risk factors of strabismus in a Chinese population-based cohort of preschool children: the Nanjing Eye Study. Br J Ophthalmol 2020; 105:1203-1210. [PMID: 32829306 DOI: 10.1136/bjophthalmol-2020-316807] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/26/2020] [Accepted: 08/02/2020] [Indexed: 12/31/2022]
Abstract
AIMS To evaluate the prevalence, incidence and their related risk factors of strabismus among preschool children in China. METHODS Children born between September 2011 and August 2012 in Yuhuatai District of Nanjing were invited to participate in the Nanjing Eye Study for a comprehensive eye examination annually since 2015. The data presented in this paper were obtained from 2015 to 2017, when these children grew from the age of 3 to 5 years. Eye examinations included visual acuity, anterior segment, posterior segment, refraction, and ocular alignment and motility. Risk factors were evaluated using univariable and multivariable logistic regression models for prevalent and incident strabismus. RESULTS In 2015, a total of 2018 children (87.7% response rate) of 2300 eligible preschoolers completed the baseline eye examination when they were 3 years old. Among the 2018 participants, 50 had strabismus (prevalence rate, 2.48%). In multivariable analysis, prevalent strabismus was independently associated with parental strabismus history (OR=11.60, p<0.001), hyperopia (OR=6.22, p<0.001), prematurity (OR=3.07, p=0.01) and astigmatism (OR=2.15, p=0.04). Among 1766 children followed up for 2 years, 63 developed strabismus (annual incidence rate, 1.78%), of whom 57 had exotropia and 6 had esotropia. In multivariable analysis, incident strabismus was significantly associated with parental strabismus history (OR=5.55, p=0.04) and prematurity (OR=3.77, p<0.001). CONCLUSIONS In this population-based cohort study, we found a higher incidence of strabismus and a higher exotropia:esotropia ratio than previous studies in preschool children. Parental strabismus history and prematurity were associated with a higher risk for both prevalent and incident strabismus.
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Affiliation(s)
- Danni Chen
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rui Li
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoxiao Li
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dan Huang
- Child Healthcare, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yue Wang
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyan Zhao
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaohan Zhang
- Ophthalmology, Wuxi Children's Hospital, Wuxi, China
| | - Qigang Sun
- Maternal and Child Healthcare Hospital of Yuhuatai District Nanjing China, Nanjing, China
| | - Qingfeng Hao
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Haohai Tong
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinyuan Yao
- The Fourth School of Clinical Medicine of Nanjing Medical University, Nanjing, China
| | - Weixiao Fan
- The Fourth School of Clinical Medicine of Nanjing Medical University, Nanjing, China
| | - Weijing Lu
- The Fourth School of Clinical Medicine of Nanjing Medical University, Nanjing, China
| | - Jingsong Dang
- The Fourth School of Clinical Medicine of Nanjing Medical University, Nanjing, China
| | - Hui Zhu
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hu Liu
- Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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15
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Çorak Eroğlu F, Oto S, Şahin Fİ, Terzi Y, Özer Kaya Ö, Tekindal MA. The Role of Heredity and the Prevalence of Strabismus in Families with Accommodative, Partial Accommodative, and Infantile Esotropia. Turk J Ophthalmol 2020; 50:143-150. [PMID: 32631000 PMCID: PMC7338743 DOI: 10.4274/tjo.galenos.2019.49204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Objectives: To investigate the prevalence of strabismus in families of a proband with accommodative, partial accommodative, or infantile esotropia (IET), and to evaluate the mode of inheritance and the role of consanguineous marriages in this prevalence. Materials and Methods: Families of probands with comitant strabismus were invited to participate in the study. The family members of 139 subjects with accommodative esotropia (AET), 55 with partial accommodative esotropia (PAET), and 21 with IET agreed to participate. Detailed family trees were constructed. The first- and second-degree relatives were invited for a complete ophthalmological examination, and 518 individuals from 168 families were evaluated. The role of consanguinity, the presence of tropia, phoria (≥8 PD), microtropia, and hypermetropia (≥3.00 D) among first- and second-degree relatives were analyzed. Results: A non-Mendelian pattern was found in 49 families (23%), an autosomal dominant pattern in 39 families (18%), and an autosomal recessive pattern in 6 families (3%). The prevalence of consanguineous marriages among parents of probands was 18.1%, 22.6%, and 14.3% in the AET, PAET, and IET groups, respectively (p=0.652). The prevalence of strabismus in first-degree relatives was 58.9%, 45.5%, and 38.1%, respectively (p=0.07). The prevalence of microtropia in probands’ siblings was significantly higher in the AET group (p=0.034). Conclusion: Sporadic cases and non-Mendelian inheritance were more frequent than autosomal recessive inheritance. Autosomal recessive inheritance was found not to be frequent in consanguineous marriages. The prevalence of strabismus and microtropia was significantly higher in families of esotropia cases than in the general population.
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Affiliation(s)
| | - Sibel Oto
- Başkent University Faculty of Medicine, Department of Ophthalmology, Ankara, Turkey
| | - Feride İffet Şahin
- Başkent University Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey
| | - Yunus Terzi
- Başkent University Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey
| | - Özge Özer Kaya
- Tepecik Training and Research Hospital, Genetic Diagnostic Center, İzmir, Turkey
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16
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Yoon L, Kim HY, Kwak MJ, Park KH, Bae MH, Lee Y, Nam SO, Choi HY, Kim YM. Utility of Magnetic Resonance Imaging (MRI) in Children With Strabismus. J Child Neurol 2019; 34:574-581. [PMID: 31111751 DOI: 10.1177/0883073819846807] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Magnetic resonance imaging (MRI) of the brain can provide valuable information about structural abnormalities in strabismus. The aim of this study was to evaluate the utility of MRI in this regard and to identify risk factors for abnormal MRI results in children with strabismus. METHODS A retrospective analysis of children <18 years of age presenting with strabismus, who underwent brain MRI at Pusan National University Hospital (Busan, Korea) between January 2012 and March 2017, was performed. Clinical characteristics, MRI results, and ophthalmologic findings were reviewed. Findings were classified as normal or abnormal according to MRI results. Additionally, patients were divided according to age to compare characteristics of infantile and childhood strabismus. RESULTS A total of 90 patients (47 [52.2%] male, 43 [47.8%] female; mean age, 2.19 ± 0.53 years) were enrolled. Of those, 64 (71.1%) presented with normal and 26 (28.9%) with abnormal MRI results. The age at presentation was lower and abnormal findings on fundus examination were more common in the abnormal MRI group (P = .002 and P = .008, respectively). Among the patients, 46 (51.1%) had infantile strabismus and 44 (48.9%) had childhood strabismus. Global developmental delays, speech delays, and MRI abnormalities were more common in patients with infantile than in those with childhood strabismus. Ptosis and headaches were more common in patients with childhood strabismus (P = .025, P = .025, respectively). CONCLUSION Brain MRI was helpful for accurate diagnosis and treatment of strabismus in younger children, those with abnormal findings on fundus examination, and infants with developmental, especially speech, delays.
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Affiliation(s)
- Lira Yoon
- 1 Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Hye-Young Kim
- 1 Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Min Jung Kwak
- 1 Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Kyung Hee Park
- 1 Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Mi Hye Bae
- 1 Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Yunjin Lee
- 2 Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Korea
| | - Sang Ook Nam
- 2 Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Yangsan, Korea
| | - Hee Young Choi
- 3 Department of Ophthalmology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
| | - Young Mi Kim
- 1 Department of Pediatrics, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, South Korea
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17
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Plotnikov D, Shah RL, Rodrigues JN, Cumberland PM, Rahi JS, Hysi PG, Atan D, Williams C, Guggenheim JA. A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus. Hum Genet 2019; 138:723-737. [PMID: 31073882 PMCID: PMC6611893 DOI: 10.1007/s00439-019-02022-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 04/20/2019] [Indexed: 12/31/2022]
Abstract
Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus.
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Affiliation(s)
- Denis Plotnikov
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Rupal L Shah
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Jamille N Rodrigues
- Population Health Sciences, Bristol Medical School, University of Bristol, 1-5 Whiteladies Road, Bristol, BS8 1NU, UK
| | - Phillippa M Cumberland
- Life Course Epidemiology and Biostatistics Section, Institute of Child Health, University College London, London, WC1N 1EH, UK
- Ulverscroft Vision Research Group, University College London Institute of Child Health, London, WC1N 1EH, UK
| | - Jugnoo S Rahi
- Life Course Epidemiology and Biostatistics Section, Institute of Child Health, University College London, London, WC1N 1EH, UK
- Ulverscroft Vision Research Group, University College London Institute of Child Health, London, WC1N 1EH, UK
- University College London Great Ormond Street Institute of Child Health, London, WC1N 3JH, UK
- National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, WC1E 6BT, UK
| | - Pirro G Hysi
- Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Hospital, London, SE1 7EH, UK
| | - Denize Atan
- Population Health Sciences, Bristol Medical School, University of Bristol, 1-5 Whiteladies Road, Bristol, BS8 1NU, UK
| | - Cathy Williams
- Population Health Sciences, Bristol Medical School, University of Bristol, 1-5 Whiteladies Road, Bristol, BS8 1NU, UK.
| | - Jeremy A Guggenheim
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, CF24 4HQ, UK.
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18
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Ye XC, van der Lee R, Wasserman WW. Curation and bioinformatic analysis of strabismus genes supports functional heterogeneity and proposes candidate genes with connections to RASopathies. Gene 2019; 697:213-226. [PMID: 30772522 DOI: 10.1016/j.gene.2019.02.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 01/03/2019] [Accepted: 02/01/2019] [Indexed: 12/21/2022]
Abstract
Strabismus refers to the misalignment of the eyes and occurs in 2-4% of individuals. The low-resolution label "strabismus" covers a range of heterogeneous defects, which makes it challenging to unravel this condition. Consequently a coherent understanding of the causes is lacking. Here, we attempt to gain a better understanding of the underlying genetics by combining gene curation, diverse bioinformatic analyses (including gene ontology, pathway mapping, expression and network-based methods) and literature review. Through a phenotype-based curation process, we identify high-confidence and permissive sets of 54 and 233 genes potentially involved in strabismus. These genes can be grouped into 10 modules that together span a heterogeneous set of biological and molecular functions, and can be linked to clinical sub-phenotypes. Multiple lines of evidence associate retina and cerebellum biology with the strabismus genes. We further highlight a potential role of the Ras-MAPK pathway. Independently, sets of 11 genes and 15 loci tied to strabismus with definitive genetic basis have been compiled from the literature. We identify strabismus candidate genes for 5 of the 15 reported loci (CHD7; SLC9A6; COL18A1, COL6A2; FRY, BRCA2, SPG20; PARK2). Finally, we synthesize a Strabismus Candidate Gene Collection, which together with our curated gene sets will serve as a resource for future research. The results of this informatics study support the heterogeneity and complexity of strabismus and point to specific biological pathways and brain regions for future focus.
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Affiliation(s)
- Xin Cynthia Ye
- Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Robin van der Lee
- Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
| | - Wyeth W Wasserman
- Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
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19
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Shaaban S, MacKinnon S, Andrews C, Staffieri SE, Maconachie GDE, Chan WM, Whitman MC, Morton SU, Yazar S, MacGregor S, Elder JE, Traboulsi EI, Gottlob I, Hewitt AW, Strabismus Genetics Research Consortium, Hunter DG, Mackey DA, Engle EC. Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect. Invest Ophthalmol Vis Sci 2018; 59:4054-4064. [PMID: 30098192 PMCID: PMC6088800 DOI: 10.1167/iovs.18-24082] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 06/19/2018] [Indexed: 11/24/2022] Open
Abstract
Purpose To identify genetic variants conferring susceptibility to esotropia. Esotropia is the most common form of comitant strabismus, has its highest incidence in European ancestry populations, and is believed to be inherited as a complex trait. Methods White European American discovery cohorts with nonaccommodative (826 cases and 2991 controls) or accommodative (224 cases and 749 controls) esotropia were investigated. White European Australian and United Kingdom cohorts with nonaccommodative (689 cases and 1448 controls) or accommodative (66 cases and 264 controls) esotropia were tested for replication. We performed a genome-wide case-control association study using a mixed linear additive model. Meta-analyses of discovery and replication cohorts were then conducted. Results A significant association with nonaccommodative esotropia was discovered (odds ratio [OR] = 1.41, P = 2.84 × 10-09) and replicated (OR = 1.23, P = 0.01) at rs2244352 [T] located within intron 1 of the WRB (tryptophan rich basic protein) gene on chromosome 21 (meta-analysis OR = 1.33, P = 9.58 × 10-11). This single nucleotide polymorphism (SNP) is differentially methylated, and there is a statistically significant skew toward paternal inheritance in the discovery cohort. Meta-analysis of the accommodative discovery and replication cohorts identified an association with rs912759 [T] (OR = 0.59, P = 1.89 × 10-08), an intergenic SNP on chromosome 1p31.1. Conclusions This is the first genome-wide association study (GWAS) to identify significant associations in esotropia and suggests a parent-of-origin effect. Additional cohorts will permit replication and extension of these findings. Future studies of rs2244352 and WRB should provide insight into pathophysiological mechanisms underlying comitant strabismus.
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Affiliation(s)
- Sherin Shaaban
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States
- Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States
- Dubai Harvard Foundation for Medical Research, Boston, Massachusetts, United States
| | - Sarah MacKinnon
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Caroline Andrews
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
- Howard Hughes Medical Institute, Chevy Chase, Maryland, United States
| | - Sandra E. Staffieri
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
- Department of Ophthalmology, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Gail D. E. Maconachie
- Department of Neuroscience, The University of Leicester Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom
| | - Wai-Man Chan
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
- Howard Hughes Medical Institute, Chevy Chase, Maryland, United States
| | - Mary C. Whitman
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - Sarah U. Morton
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
| | - Seyhan Yazar
- Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
- Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia
| | - Stuart MacGregor
- Stastical Genetics Laboratory, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - James E. Elder
- Department of Ophthalmology, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia
- Department of Pediatrics, The University of Melbourne, Parkville, Victoria, Australia
| | - Elias I. Traboulsi
- Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
| | - Irene Gottlob
- Department of Neuroscience, The University of Leicester Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom
| | - Alex W. Hewitt
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia
- Department of Ophthalmology, School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
| | - Strabismus Genetics Research Consortium
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States
- Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States
- Dubai Harvard Foundation for Medical Research, Boston, Massachusetts, United States
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
- Howard Hughes Medical Institute, Chevy Chase, Maryland, United States
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
- Department of Ophthalmology, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia
- Department of Neuroscience, The University of Leicester Ulverscroft Eye Unit, University of Leicester, Leicester, United Kingdom
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, United States
- Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
- Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia
- Stastical Genetics Laboratory, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Department of Pediatrics, The University of Melbourne, Parkville, Victoria, Australia
- Department of Ophthalmology, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
- Department of Ophthalmology, School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, United States
| | - David G. Hunter
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States
| | - David A. Mackey
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, Western Australia, Australia
- Department of Ophthalmology, School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
| | - Elizabeth C. Engle
- Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States
- F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, United States
- Department of Neurology, Harvard Medical School, Boston, Massachusetts, United States
- Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts, United States
- Howard Hughes Medical Institute, Chevy Chase, Maryland, United States
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, United States
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Zhang J, Matsuo T. MGST2 and WNT2 are candidate genes for comitant strabismus susceptibility in Japanese patients. PeerJ 2017; 5:e3935. [PMID: 29062608 PMCID: PMC5649647 DOI: 10.7717/peerj.3935] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 09/26/2017] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND/AIM Strabismus is a common condition with misalignment between two eyes that may lead to decrease of visual acuity, lack of binocularity, and diplopia. It is caused by heterogeneous environmental and genetic risk factors. Our previous research has identified new chromosomal susceptibility loci in 4q28.3 and 7q31.2 regions for comitant strabismus in Japanese families. We conducted a verification study by linkage analysis to narrow the chromosomal loci down to a single gene. METHODS From Japanese and U.S. databases, 24 rsSNPs and 233 rsSNPs were chosen from the 4q28.3 and 7q31.2 region, respectively, and were typed in 108 affected subjects and 96 unaffected subjects of 58 families with primary and non-syndromic comitant strabismus. Three major analytical methods were used: transmission disequilibrium test (TDT), TDT allowing for errors (TDTae), and linkage analysis under dominant and recessive inheritance. RESULTS The SNPs with significant P values in TDT and TDTae were located solely at the gene, microsomal glutathione S-transferase 2 (MGST2), on chromosome 4q28.3 locus. In contrast, significant SNPs were dispersed in a few genes, containing wingless-type MMTV integration site family member 2 (WNT2), on chromosome 7q31.2 locus. The distribution of significant SNPs on the 7q31.2 locus showed that only the ST7 to WNT2 region in the same big haplotype block contained significant SNPs for all three methods of linkage analysis. CONCLUSIONS This study suggests that MGST2 and WNT2 are potential candidates for comitant strabismus in Japanese population.
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Affiliation(s)
- Jingjing Zhang
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan
| | - Toshihiko Matsuo
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Okayama, Japan
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Gong HM, Wang J, Xu J, Zhou ZY, Li JW, Chen SF. Identification of rare paired box 3 variant in strabismus by whole exome sequencing. Int J Ophthalmol 2017; 10:1223-1228. [PMID: 28861346 DOI: 10.18240/ijo.2017.08.06] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/24/2017] [Indexed: 11/23/2022] Open
Abstract
AIM To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.
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Affiliation(s)
- Hui-Min Gong
- Ophthalmologic Center, Qingdao Municipal Hospital, the Affiliated Municipal Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Jing Wang
- Department of Ophthalmology, Dezhou People's Hospital, Dezhou 253000, Shandong Province, China
| | - Jing Xu
- Department of Ophthalmology, Weifang People's Hospital, Weifang 261041, Shandong Province, China
| | - Zhan-Yu Zhou
- Ophthalmologic Center, Qingdao Municipal Hospital, the Affiliated Municipal Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Jing-Wen Li
- Ophthalmologic Center, Qingdao Municipal Hospital, the Affiliated Municipal Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Shu-Fang Chen
- Department of Medical Equipment, Weifang People's Hospital, Weifang 261041, Shandong Province, China
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Chaudhuri Z, John J, Aneja S, Thelma BK. Pedigree Analysis of Familial Primary Concomitant Horizontal Strabismus in Northern India. Strabismus 2017; 25:200-213. [PMID: 28796570 DOI: 10.1080/09273972.2017.1350865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
PURPOSE Familial clustering of common forms of primary strabismus like esotropia (ET) and exotropia (XT) is observed in a proportion of the strabismus cohort. The genetic components of this remain unidentified. Linkage studies have demonstrated susceptibility locus for primary strabismus at the STBMS1 locus on 7p22.1 as well as other loci on 4q28.3 and 7q31.2. Recently next generation sequencing (NGS) technology has emerged as a powerful tool in discovery genomics and a large number of novel disease-causing variants are being reported. In this study, we recruited informative families for subsequent genetic analysis for disease-causing variant identification. METHODS All consecutive families with two or more affected members with primary concomitant horizontal strabismus were prospectively recruited at the ophthalmic outpatients department (OPD) of Lady Hardinge Medical College, New Delhi, from August 2014 to February 2017. Detailed phenotypic evaluation and pedigree documentation was performed. RESULTS Of the 39 recruited families of north Indian origin, 18 families each had affected family members demonstrating either ET or XT. 100% concordance of the phenotype in the affected family members was observed in these families. While vertical transmission was observed in 17/18 families with XT, 7 with ET had affected members across one generation, 2 demonstrated consanguineous pedigree, and 2 comprised identical twin families. In 3 families, a combination of ET and XT was noted. This comprised one family with the ET and XT patients being from 2 separate arms of the family related by marriage, one family where one sibling had XT and the other had ET, and another family where the maternal aunt of the affected proband with ET had XT. CONCLUSIONS Subjects with familial primary concomitant strabismus recruited in this study may provide a valuable resource to unravel the genetic determinants of this condition, which is a common disorder of early childhood with high ophthalmic morbidity.
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Affiliation(s)
- Zia Chaudhuri
- a Lady Hardinge Medical College , University of Delhi , New Delhi , India.,b Department of Genetics , University of Delhi South Campus , New Delhi, India
| | - Jibin John
- b Department of Genetics , University of Delhi South Campus , New Delhi, India
| | - Satinder Aneja
- a Lady Hardinge Medical College , University of Delhi , New Delhi , India
| | - B K Thelma
- b Department of Genetics , University of Delhi South Campus , New Delhi, India
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Min X, Fan H, Zhao G, Liu G. Identification of 2 Potentially Relevant Gene Mutations Involved in Strabismus Using Whole-Exome Sequencing. Med Sci Monit 2017; 23:1719-1724. [PMID: 28391287 PMCID: PMC5395132 DOI: 10.12659/msm.902823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Background The etiology of strabismus has a genetic component. Our study aimed to localize the candidate causative gene mutant in a Chinese family with strabismus and to describe its underlying etiology. Material/Methods Genomic DNA was extracted from the affected individual and his parents in a Chinese pedigree with strabismus. The resulting exomes were sequenced by whole-exome sequencing. After variant calling and filtering, the candidate causative gene mutations were selected for the rarity and predicted damaging effect, which complied with the model of recessive disease transmission. Results We examined a Chinese strabismus pedigree with the parents unaffected and 2 offspring affected. Whole-exome sequencing and bioinformatics filtering identified 2 variants including Abelson helper integration site 1 (AHI1) gene and nebulin (NEB) gene. The variant in the AHI1 gene, c.A3257G (p.E1086G), and the altered amino acid had a damaging effect on the encoded protein predicted by Polyphen2. Moreover, this change was located in the conserved SH3 domain of AHI1. Biallelic pathogenic variant in AHI1 gene can cause Joubert syndrome-related disorders with oculomotor apraxia characteristics. Additionally, c.A914G mutation was found in nebulin (NEB) gene. Therefore, we concluded that AHI1 c.3257A>G and NEB c.914 A>G were potential causal variants in this strabismus pedigree. Conclusions We detected an AHI1 homozygous mutation in the affected individual. Whole-exome sequencing is a powerful way to identify causally relevant genes, improving the understanding of this disorder.
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Affiliation(s)
- Xiangrong Min
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland).,Department of Ophthalmology, Jining No. 1 People's Hospital, Jining, Shandong, China (mainland)
| | - Haiying Fan
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Guiqiu Zhao
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Guixiang Liu
- Department of Ophthalmology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
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Gulati S, Andrews CA, Apkarian AO, Musch DC, Lee PP, Stein JD. Effect of gestational age and birth weight on the risk of strabismus among premature infants. JAMA Pediatr 2014; 168:850-6. [PMID: 25048624 PMCID: PMC4339677 DOI: 10.1001/jamapediatrics.2014.946] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
IMPORTANCE Strabismus causes irreversible vision loss if not detected and treated early. It is unclear whether birth weight (BW) and gestational age (GA) are risk factors for strabismus. OBJECTIVE To estimate the effect of BW and GA on the likelihood of premature infants developing strabismus. DESIGN, SETTING, AND PARTICIPANTS In this longitudinal cohort analysis, we monitored a group of premature children from birth to determine the proportion that developed strabismus and the timing of the first strabismus diagnosis. Multivariable Cox regression analyses assessed the relationships of BW and GA with the development of strabismus. Regression models were adjusted for other risk factors for strabismus, sociodemographic factors, and ocular comorbidities. The analysis included 38,055 otherwise healthy children born prematurely who were enrolled for more than 6 months in a nationwide US managed care network between 2001 and 2011 in communities throughout the United States. EXPOSURES Birth weight less than 2000 g or GA of 32 weeks or less. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) for strabismus with 95% CIs. RESULTS Of 38,055 otherwise healthy children who were born prematurely, 583 received a diagnosis of strabismus later in life. The cumulative incidence of strabismus was 3.0% at 5 years. Controlling for GA and other covariates, infants born with BW less than 2000 g had a 61% increased hazard (HR, 1.61; 95% CI, 1.22-2.13) of developing strabismus. Controlling for BW and other covariates, there was no significant association between strabismus and GA (HR, 0.98; 95% CI, 0.69-1.38). Among premature infants with BW of less than 2000 g, a GA of 32 weeks or less conveyed no additional increased risk for developing strabismus relative to infants born after 32 weeks (HR, 1.27; 95% CI, 0.86-1.88). In contrast, among infants with a GA of 32 weeks or less, BW of less than 2000 g conveyed a 14-fold increase in the risk of strabismus relative to BW of 2000 g or more (HR, 14.39; 95% CI, 1.99-104.14). CONCLUSIONS AND RELEVANCE Independent of GA, very low BW conferred a large increase in strabismus risk among premature infants. In contrast, independent of BW, GA did not significantly affect the risk of strabismus. Updates to existing guidelines in the pediatric and ophthalmic literature should be considered, highlighting the importance of BW rather than GA and alerting clinicians about the need for careful monitoring of premature infants with low BW for strabismus.
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Affiliation(s)
- Shilpa Gulati
- W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
| | - Chris A. Andrews
- W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
| | - Alexandra O. Apkarian
- W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
| | - David C. Musch
- W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
| | - Paul P. Lee
- W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
| | - Joshua D. Stein
- W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
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25
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Ye XC, Pegado V, Patel MS, Wasserman WW. Strabismus genetics across a spectrum of eye misalignment disorders. Clin Genet 2014; 86:103-11. [PMID: 24579652 PMCID: PMC4233980 DOI: 10.1111/cge.12367] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 02/20/2014] [Accepted: 02/24/2014] [Indexed: 01/24/2023]
Abstract
Eye misalignment, called strabismus, is amongst the most common phenotypes observed, occurring in up to 5% of individuals in a studied population. While misalignment is frequently observed in rare complex syndromes, the majority of strabismus cases are non-syndromic. Over the past decade, genes and pathways associated with syndromic forms of strabismus have emerged, but the genes contributing to non-syndromic strabismus remain elusive. Genetic testing for strabismus risk may allow for earlier diagnosis and treatment, as well as decreased frequency of surgery. We review human and model organism literature describing non-syndromic strabismus, including family, twin, linkage, and gene expression studies. Recent advances in the genetics of Duane retraction syndrome are considered, as relatives of those impacted show elevated familial rates of non-syndromic strabismus. As whole genome sequencing efforts are advancing for the discovery of the elusive strabismus genes, this overview is intended to support the interpretation of the new findings.
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Affiliation(s)
- X C Ye
- Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, Vancouver, BC, Canada
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Georges A, Cambisano N, Ahariz N, Karim L, Georges M. A genome scan conducted in a multigenerational pedigree with convergent strabismus supports a complex genetic determinism. PLoS One 2014; 8:e83574. [PMID: 24376720 PMCID: PMC3871668 DOI: 10.1371/journal.pone.0083574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Accepted: 11/06/2013] [Indexed: 11/26/2022] Open
Abstract
A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree including all affected individuals were genotyped using a SNP array interrogating > 300,000 common SNPs. We conducted parametric and non-parametric linkage analyses assuming segregation of an autosomal dominant mutation, yet allowing for incomplete penetrance and phenocopies. We detected two chromosome regions with near-suggestive evidence for linkage, respectively on chromosomes 8 and 18. The chromosome 8 linkage implied a penetrance of 0.80 and a rate of phenocopy of 0.11, while the chromosome 18 linkage implied a penetrance of 0.64 and a rate of phenocopy of 0. Our analysis excludes a simple genetic determinism of strabismus in this pedigree.
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Affiliation(s)
- Anouk Georges
- Department of Ophtalmology, Faculty of Medicine, University of Liège (CHU), Liège, Belgium
| | - Nadine Cambisano
- Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium
| | - Naïma Ahariz
- Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium
| | - Latifa Karim
- GIGA-R Genotranscriptomics Core Faclity, University of Liège (B34), Liège, Belgium
| | - Michel Georges
- Unit of Animal Genomics, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium
- * E-mail:
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Comitant strabismus: Perspectives, present and future. Saudi J Ophthalmol 2013; 26:265-70. [PMID: 23961004 DOI: 10.1016/j.sjopt.2012.05.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2012] [Revised: 05/08/2012] [Accepted: 05/15/2012] [Indexed: 11/24/2022] Open
Abstract
Comitant strabismus is a common condition affecting infants, children and adults. Its impact on the affected patient may be severe resulting in visual loss, lack of binocularity, diplopia, social stigma and multiple corrective surgeries within the affected individual's lifespan. It is therefore important that this prevalent disorder should be better understood. We review the current understanding of the demographics and what is known of the etiology, risk factors and genetics of strabismus. We stress the importance of careful clinical assessment in classifying strabismus, and the common pitfalls in the measurement and pre-operative sensory work-up of the strabismic patient. The fact strabismus is comitant does not indicate it is benign: acute onset of comitant esotropia may be a presenting sign of pontine or cerebellar tumor. Lastly, we review the impact of genetics on our understanding of strabismus. While the causes of many types of congenital incomitant strabismus have been elucidated through careful observation and genetic screening, the genetics of comitant strabismus are more complex and multifactorial. Only through careful study and recruitment of large groups of affected individuals and families can we start to answer the question: why is this group of patients pre-disposed to develop strabismus. Doing so will help identify patients at risk, to spare them from the significant morbidity associated with this common disorder.
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Altick AL, Feng CY, Schlauch K, Johnson LA, von Bartheld CS. Differences in gene expression between strabismic and normal human extraocular muscles. Invest Ophthalmol Vis Sci 2012; 53:5168-77. [PMID: 22786898 DOI: 10.1167/iovs.12-9785] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE Strabismic extraocular muscles (EOMs) differ from normal EOMs in structural and functional properties, but the gene expression profile of these two types of EOM has not been examined. Differences in gene expression may inform about causes and effects of the strabismic condition in humans. METHODS EOM samples were obtained during corrective surgery from patients with horizontal strabismus and from deceased organ donors with normal EOMs. Microarrays and quantitative PCR identified significantly up- and down-regulated genes in EOM samples. Analysis was performed on probe sets with more than 3-fold differential expression between normal and strabismic samples, with an adjusted P value of ≤ 0.05. RESULTS Microarray analysis showed that 604 genes in these samples had significantly different expression. Expression predominantly was upregulated in genes involved in extracellular matrix structure, and down-regulated in genes related to contractility. Expression of genes associated with signaling, calcium handling, mitochondria function and biogenesis, and energy homeostasis also was significantly different between normal and strabismic EOM. Skeletal muscle PCR array identified 22 (25%) of 87 muscle-specific genes that were significantly down-regulated in strabismic EOMs; none was significantly upregulated. CONCLUSIONS Differences in gene expression between strabismic and normal human EOMs point to a relevant contribution of the peripheral oculomotor system to the strabismic condition. Decreases in expression of contractility genes and increases of extracellular matrix-associated genes indicate imbalances in EOM structure. We conclude that gene regulation of proteins fundamental to contractile mechanics and extracellular matrix structure is involved in pathogenesis and/or consequences of strabismus, suggesting potential novel therapeutic targets.
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Affiliation(s)
- Amy L Altick
- Department of Physiology & Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
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Heritability of strabismus: genetic influence is specific to eso-deviation and independent of refractive error. Twin Res Hum Genet 2012; 15:624-30. [PMID: 22877876 DOI: 10.1017/thg.2012.22] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Strabismus represents a complex oculomotor disorder characterized by the deviation of one or both eyes and poor vision. A more sophisticated understanding of the genetic liability of strabismus is required to guide searches for associated molecular variants. In this classical twin study of 1,462 twin pairs, we examined the relative influence of genes and environment in comitant strabismus, and the degree to which these influences can be explained by factors in common with refractive error. Participants were examined for the presence of latent ('phoria') and manifest ('tropia') strabismus using cover-uncover and alternate cover tests. Two phenotypes were distinguished: eso-deviation (esophoria and esotropia) and exo-deviation (exophoria and exotropia). Structural equation modeling was subsequently employed to partition the observed phenotypic variation in the twin data into specific variance components. The prevalence of eso-deviation and exo-deviation was 8.6% and 20.7%, respectively. For eso-deviation, the polychoric correlation was significantly greater in monozygotic (MZ) (r = 0.65) compared to dizygotic (DZ) twin pairs (r = 0.33), suggesting a genetic role (p = .003). There was no significant difference in polychoric correlation between MZ (r = 0.55) and DZ twin pairs (r = 0.53) for exo-deviation (p = .86), implying that genetic factors do not play a significant role in the etiology of exo-deviation. The heritability of an eso-deviation was 0.64 (95% CI 0.50-0.75). The additive genetic correlation for eso-deviation and refractive error was 0.13 and the bivariate heritability (i.e., shared variance) was less than 1%, suggesting negligible shared genetic effect. This study documents a substantial heritability of 64% for eso-deviation, yet no corresponding heritability for exo-deviation, suggesting that the genetic contribution to strabismus may be specific to eso-deviation. Future studies are now needed to identify the genes associated with eso-deviation and unravel their mechanisms of action.
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Infantile esotropia could be oligogenic and allelic with Duane retraction syndrome. Mol Vis 2011; 17:1997-2002. [PMID: 21850174 PMCID: PMC3154136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Accepted: 07/14/2011] [Indexed: 10/25/2022] Open
Abstract
PURPOSE To describe phenotyping and linkage analysis results for available members from a consanguineous nuclear family with hereditary congenital strabismus. METHODS Both parents and all 12 children underwent clinical examination. Available affected and several unaffected family members had venous blood sampling for DNA extraction and 10K single nucleotide polymorphism (SNP) genotyping (Affymetrix Gene Chip® Human). Multipoint logarithm of the odds (LOD) score calculations were performed assuming an autosomal recessive mode of inheritance with 100% penetrance and disease allele frequency of 0.01%. RESULTS Three children had non-syndromic large-angle infantile esotropia without significant hyperopia. A fourth child had left esotropic Duane retraction syndrome. A fifth child who had esotropia in the setting of prematurity and childhood poliomyelitis was excluded from the analysis. A sixth child had keratoconus and was excluded. Both parents and the remaining 6 children had no significant orthoptic or ophthalmic findings. Using linkage analysis including the 4 esotropic children, disease loci were mapped to regions on chromosomes 3p26.3-26.2 and 6q24.2-25.1 using multipoint linkage analysis with LOD scores of 3.18 and 3.25 respectively. Linkage to these regions persisted when the esotropic Duane retraction syndrome patient was excluded from the linkage analysis (LOD scores of 2.00 and 2.32, respectively). CONCLUSIONS Non-syndromic infantile esotropia could be related to susceptibility loci on chromosomal regions 3p26.3-26.2 and 6q24.2-25.1 and may share alleles that underlie Duane retraction syndrome.
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Khan AO, Shinwari J, Abu Dhaim N, Khalil D, Al Sharif L, Al Tassan N. Potential linkage of different phenotypic forms of childhood strabismus to a recessive susceptibility locus (16p13.12-p12.3). Mol Vis 2011; 17:971-6. [PMID: 21541264 PMCID: PMC3084218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2011] [Accepted: 04/04/2011] [Indexed: 11/18/2022] Open
Abstract
PURPOSE To perform linkage analysis on an inbred family with members who exhibit different phenotypic forms of childhood strabismus. METHODS Prospective clinical examination and linkage analysis. RESULTS three of the ten siblings and their cousin each had a different phenotypic form of childhood strabismus: infantile esotropia with convergence excess, esotropia associated with anisometropic amblyopia, unilateral esotropic Duane syndrome, and monocular elevation deficiency. Linkage analysis for the four strabismic individuals, an unaffected sibling, and the unaffected parents identified a single disease locus on chromosome 16p13.12-p12.3 (Ensembl cytogenetic band) with a 2.5 maximum logarithm of odds score. The region is 6 MB in size and comprises 80 genes. DISCUSSION Linkage analysis in this unique family suggests that childhood strabismus can be recessive and that different phenotypic forms of childhood strabismus can share the same underlying genotype.
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Affiliation(s)
- Arif O. Khan
- Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia,Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Jameela Shinwari
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nada Abu Dhaim
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Dania Khalil
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Latifa Al Sharif
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nada Al Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Wilmer JB, Backus BT. Genetic and environmental contributions to strabismus and phoria: evidence from twins. Vision Res 2009; 49:2485-93. [PMID: 19679148 PMCID: PMC2757458 DOI: 10.1016/j.visres.2009.08.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2009] [Revised: 08/04/2009] [Accepted: 08/04/2009] [Indexed: 01/15/2023]
Abstract
The causes of manifest (strabismus) and latent (phoria) misalignment of the visual axes are incompletely understood. We calculated genetic and environmental contributions to strabismus based upon a critical review and quantitative meta-analysis of previous strabismus twin studies (n=3418 twin pairs) and calculated contributions to phoria based upon a new twin study (n=307 twin pairs). Our results suggest that genetic liability is necessary to develop strabismus, whereas environmental factors are sufficient to cause most phorias. The different etiologies implied by this work suggest that strabismus and phoria should be carefully distinguished in epidemiological work.
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Shaaban S, Matsuo T, Strauch K, Ohtsuki H. Investigation of parent-of-origin effect in comitant strabismus using MOD score analysis. Mol Vis 2009; 15:1351-8. [PMID: 19597570 PMCID: PMC2709426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2009] [Accepted: 07/05/2009] [Indexed: 11/29/2022] Open
Abstract
PURPOSE Comitant strabismus is a common pediatric ophthalmic disorder with both genetic and non-genetic factors contributing to its etiology. The aim of the current study is to investigate the phenomenon of a parent-of-origin effect, genomic imprinting, as a possible mode of inheritance in comitant strabismus. METHODS We performed parametric genome-wide MOD score (model-maximized LOD score) linkage analysis, incorporating imprinting effects, for 382 microsatellite markers in a sample of 258 individuals (117 males and 141 females) from 55 Japanese families with comitant strabismus. We included individuals as affected patients if they presented with comitant esotropia or exotropia based on ophthalmic examination, history taking, or analysis of medical records. RESULTS Significant or suggestive linkage to comitant strabismus with evidence of maternal or paternal imprinting was detected at D4S1575 (4q28.3), D7S486 (7q31.2), D11S1320 (11q24.2), D12S324 (12q24.32), and D19S420 (19q13.11). Using the MOD score approach, we found new evidence of linkage to comitant strabismus at three loci on chromosomes 6q26 (MOD(imp)=MOD(reg)=3.75), 12q24.32 (MOD(imp)=3.36), and 19q13.11 (MOD(imp)=3.79). CONCLUSIONS The results suggest that the parent-of-origin effect may play a role in the etiology of comitant strabismus.
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Affiliation(s)
- Sherin Shaaban
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Japan,Department of Ophthalmology, Mansoura Ophthalmic Center, Mansoura University, El-Mansoura City, Egypt
| | - Toshihiko Matsuo
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Japan
| | - Konstantin Strauch
- Institute of Medical Biometry and Epidemiology, Philipps University Marburg, Marburg, Germany
| | - Hiroshi Ohtsuki
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama City, Japan
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Abstract
The field of molecular genetics is evolving to encompass techniques that are directly relevant to the diagnosis and management of eye disease. Therefore, pediatric ophthalmologists must have a knowledge base that includes basic genetic concepts and their application to current clinical care.
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Affiliation(s)
- Kathryn Bollinger
- Department of Pediatric Ophthalmology and Strabismus, Cole Eye Institute, Cleveland, Ohio 44195, USA
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Abstract
Strabismus (misalignment of the eyes; also known as "squint") comprises a common heterogeneous group of disorders characterised by a constant or intermittent ocular deviation often associated with amblyopia (uniocular failure of normal visual development) and reduced or absent binocular vision. The associated poor cosmetic appearance may also interfere with social and psychological development. Extensive twin and family studies suggest a significant genetic component to the aetiology of strabismus. The complexity of the molecular basis of strabismus is now beginning to be elucidated with the identification of genetic loci and disease causing genes. Currently greater insights have been gained into the incomitant subtype (differing magnitude of ocular misalignment according to direction of gaze), whereas less is known about the pathogenesis of the more common childhood concomitant strabismus. It is hoped that a greater understanding of the molecular genetics of these disorders will lead to improved knowledge of disease mechanisms and ultimately to more effective treatment. The aim of this paper is to review current knowledge of the molecular genetics of both incomitant and concomitant strabismus.
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Affiliation(s)
- M Michaelides
- Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
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