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Bourgois A, Bizaoui V, Colson C, Vincent-Devulder A, Molin A, Gérard M, Gruchy N. Phenotypic and genotypic characterization of 1q21.1 copy number variants: A report of 34 new individuals and literature review. Am J Med Genet A 2024; 194:e63457. [PMID: 37881147 DOI: 10.1002/ajmg.a.63457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/01/2023] [Accepted: 10/12/2023] [Indexed: 10/27/2023]
Abstract
Recurrent 1q21.1 copy number variants (CNVs) have been associated with a wide spectrum of clinical features, ranging from normal phenotype to moderate intellectual disability, with congenital anomalies and dysmorphic features. They are often inherited from unaffected parents and the pathogenicity is difficult to assess. We describe the phenotypic and genotypic data for 34 probands carrying CNVs in the 1q21.1 chromosome region (24 duplications, 8 deletions and 2 triplications). We also reviewed 89 duplications, 114 deletions and 5 triplications described in the literature, at variable 1q21.1 locations. We aimed to identify the most highly associated clinical features to determine the phenotypic expression in affected individuals. Developmental delay or learning disabilities and neuropsychiatric disorders were common in patients with deletions, duplications and triplications of 1q21.1. Mild dysmorphic features common in these CNVs include a prominent forehead, widely spaced eyes and a broad nose. The CNVs were mostly inherited from apparently unaffected parents. Almost half of the CNVs were distal, overlapping with a common minimal region of 1.2 Mb. We delineated the clinical implications of 1q21.1 CNVs and confirmed that these CNVs are likely pathogenic, although subject to incomplete penetrance and variable expressivity. Long-term follow-up should be performed to each newly diagnosed case, and prenatal genetic counseling cautiously discussed, as it remains difficult to predict the phenotype in the event of an antenatal diagnosis.
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Affiliation(s)
- Alexia Bourgois
- Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, UR 7450 BioTARGen, FHU G4 Genomics, Caen, France
| | | | - Cindy Colson
- CHU Lille, University of Lille, EA7364, Lille, France
| | - Aline Vincent-Devulder
- Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, UR 7450 BioTARGen, FHU G4 Genomics, Caen, France
| | - Arnaud Molin
- Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, UR 7450 BioTARGen, FHU G4 Genomics, Caen, France
| | - Marion Gérard
- Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, UR 7450 BioTARGen, FHU G4 Genomics, Caen, France
| | - Nicolas Gruchy
- Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, UR 7450 BioTARGen, FHU G4 Genomics, Caen, France
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Huang TT, Xu HF, Wang SY, Lin WX, Tung YH, Khan KU, Zhang HH, Guo H, Zheng G, Zhang G. Identification of 1q21.1 microduplication in a family: A case report. World J Clin Cases 2023; 11:874-882. [PMID: 36818619 PMCID: PMC9928700 DOI: 10.12998/wjcc.v11.i4.874] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/21/2022] [Accepted: 01/12/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Copy number variation (CNV) has become widely recognized in recent years due to the extensive use of gene screening in developmental disorders and epilepsy research. 1q21.1 microduplication syndrome is a rare CNV disease that can manifest as multiple congenital developmental disorders, autism spectrum disorders, congenital malformations, and congenital heart defects with genetic heterogeneity.
CASE SUMMARY We reported a pediatric patient with 1q21.1 microduplication syndrome, and carried out a literature review to determine the correlation between 1q21.1 microduplication and its phenotypes. We summarized the patient’s medical history and clinical symptoms, and extracted genomic DNA from the patient, her parents, elder brother, and sister. The patient was an 8-mo-old girl who was hospitalized for recurrent convulsions over a 2-mo period. Whole exon sequencing and whole genome low-depth sequencing (CNV-seq) were then performed. Whole exon sequencing detected a 1.58-Mb duplication in the CHR1:145883867-147465312 region, which was located in the 1q21.1 region. Family analysis showed that the pathogenetic duplication fragment, which was also detected in her elder brother’s DNA originated from the mother.
CONCLUSION Whole exon sequencing combined with quantitative polymerase chain reaction can provide an accurate molecular diagnosis in children with 1q21.1 microduplication syndrome, which is of great significance for genetic counseling and early intervention.
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Affiliation(s)
- Ting-Ting Huang
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Hai-Feng Xu
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Shang-Yu Wang
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Wen-Xin Lin
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Yie-Hen Tung
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Kaleem Ullah Khan
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Hui-Hui Zhang
- Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
- Nanjing Xiaozhuang University Experimental Primary School, Nanjing 210000, Jiangsu Province, China
| | - Hu Guo
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Guo Zheng
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
| | - Gang Zhang
- Department of Neurology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
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CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations. Genes (Basel) 2021; 12:genes12091427. [PMID: 34573409 PMCID: PMC8472439 DOI: 10.3390/genes12091427] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/15/2022] Open
Abstract
To assess the potential of detecting copy number variations (CNVs) directly from exome sequencing (ES) data in diagnostic settings, we developed a CNV-detection pipeline based on ExomeDepth software and applied it to ES data of 450 individuals. Initially, only CNVs affecting genes in the requested diagnostic gene panels were scored and tested against arrayCGH results. Pathogenic CNVs were detected in 18 individuals. Most detected CNVs were larger than 400 kb (11/18), but three individuals had small CNVs impacting one or a few exons only and were thus not detectable by arrayCGH. Conversely, two pathogenic CNVs were initially missed, as they impacted genes not included in the original gene panel analysed, and a third one was missed as it was in a poorly covered region. The overall combined diagnostic rate (SNVs + CNVs) in our cohort was 36%, with wide differences between clinical domains. We conclude that (1) the ES-based CNV pipeline detects efficiently large and small pathogenic CNVs, (2) the detection of CNV relies on uniformity of sequencing and good coverage, and (3) in patients who remain unsolved by the gene panel analysis, CNV analysis should be extended to all captured genes, as diagnostically relevant CNVs may occur everywhere in the genome.
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Liu Y, Qu HQ, Chang X, Nguyen K, Qu J, Tian L, Glessner J, Sleiman PM, Hakonarson H. Deep learning prediction of attention-deficit hyperactivity disorder in African Americans by copy number variation. Exp Biol Med (Maywood) 2021; 246:2317-2323. [PMID: 34233526 DOI: 10.1177/15353702211018970] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Current understanding of the underlying molecular network and mechanism for attention-deficit hyperactivity disorder (ADHD) is lacking and incomplete. Previous studies suggest that genomic structural variations play an important role in the pathogenesis of ADHD. For effective modeling, deep learning approaches have become a method of choice, with ability to predict the impact of genetic variations involving complicated mechanisms. In this study, we examined copy number variation in whole genome sequencing from 116 African Americans ADHD children and 408 African American controls. We divided the human genome into 150 regions, and the variation intensity in each region was applied as feature vectors for deep learning modeling to classify ADHD patients. The accuracy of deep learning for predicting ADHD diagnosis is consistently around 78% in a two-fold shuffle test, compared with ∼50% by traditional k-mean clustering methods. Additional whole genome sequencing data from 351 European Americans children, including 89 ADHD cases and 262 controls, were applied as independent validation using feature vectors obtained from the African American ethnicity analysis. The accuracy of ADHD labeling was lower in this setting (∼70-75%) but still above the results from traditional methods. The regions with highest weight overlapped with the previously reported ADHD-associated copy number variation regions, including genes such as GRM1 and GRM8, key drivers of metabotropic glutamate receptor signaling. A notable discovery is that structural variations in non-coding genomic (intronic/intergenic) regions show prediction weights that can be as high as prediction weight from variations in coding regions, results that were unexpected.
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Affiliation(s)
- Yichuan Liu
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Hui-Qi Qu
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Xiao Chang
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Kenny Nguyen
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Jingchun Qu
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Lifeng Tian
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Joseph Glessner
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Patrick Ma Sleiman
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Yoon J, Mao Y. Dissecting Molecular Genetic Mechanisms of 1q21.1 CNV in Neuropsychiatric Disorders. Int J Mol Sci 2021; 22:5811. [PMID: 34071723 PMCID: PMC8197994 DOI: 10.3390/ijms22115811] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/23/2021] [Accepted: 05/25/2021] [Indexed: 11/17/2022] Open
Abstract
Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance.
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Affiliation(s)
| | - Yingwei Mao
- Department of Biology, Eberly College of Science, Pennsylvania State University, University Park, PA 16802, USA;
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Huang H, Cai M, Wang Y, Liang B, Lin N, Xu L. SNP Array as a Tool for Prenatal Diagnosis of Congenital Heart Disease Screened by Echocardiography: Implications for Precision Assessment of Fetal Prognosis. Risk Manag Healthc Policy 2021; 14:345-355. [PMID: 33542665 PMCID: PMC7851374 DOI: 10.2147/rmhp.s286001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/30/2020] [Indexed: 12/21/2022] Open
Abstract
Objective This study aimed to examine the effectiveness of the SNP array for the prenatal diagnosis of congenital heart disease (CHD) screened by echocardiography. Patients and Methods A total of 356 pregnant women with fetal congenital heart malformations revealed by echocardiography at the Center for Prenatal Diagnosis of Fujian Maternal and Children Hospital during the period from November 2016 through July 2019 were recruited. The fetuses were assigned into three cohorts, including 142 with a single cardiac malformation, 106 with multiple cardiac malformations and 108 with cardiac and extracardiac malformations. All fetuses underwent chromosomal karyotyping and SNP array simultaneously, and the effectiveness of the SNP array for the prenatal diagnosis of CHD was evaluated. Results The overall prevalence of abnormal karyotypes was 9.3% among the 356 fetuses with CHD, and a higher proportion was found in fetuses with cardiac and extracardiac malformations (18.5%) than in those with single (5.6%) or multiple cardiac malformations (4.7%) (P<0.05). Consistent with karyotype analysis, SNP array detected an additional 25 fetuses with pathogenic copy number variations (CNVs), seven with variant of unknown significance (VOUS) and seven with benign CNVs, and a lower proportion of abnormal CNV was found in fetuses with a single cardiac malformation (4.2%) than in those with multiple cardiac malformations (9.4%) or cardiac and extracardiac malformations (14.8%) (P<0.05). Among the 33 fetuses with chromosomal abnormality, postnatal follow-up showed termination of pregnancy in 25 with pathogenic CNVs, one with VOUS, and six with normal karyotypes and SNP array findings but severe multiple malformations by ultrasonography. Conclusion SNP array increases the overall detection of abnormal CNVs by 9%, which improves the detection of CNVs associated with CHD. SNP array may serve as a tool for prenatal diagnosis of CHD that facilitates the discovery of pathogenic genes associated with CHD and provide valuable insights into the precision assessment of fetal prognosis during the prenatal counseling.
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Affiliation(s)
- Hailong Huang
- Center for Prenatal Diagnosis, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People's Republic of China.,Fujian Key Laboratory for Prenatal Diagnosis and Birth Defects, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Meiying Cai
- Center for Prenatal Diagnosis, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People's Republic of China.,Fujian Key Laboratory for Prenatal Diagnosis and Birth Defects, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Yan Wang
- Center for Prenatal Diagnosis, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People's Republic of China.,Fujian Key Laboratory for Prenatal Diagnosis and Birth Defects, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Bin Liang
- Center for Prenatal Diagnosis, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People's Republic of China.,Fujian Key Laboratory for Prenatal Diagnosis and Birth Defects, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Na Lin
- Center for Prenatal Diagnosis, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People's Republic of China.,Fujian Key Laboratory for Prenatal Diagnosis and Birth Defects, Fuzhou 350001, Fujian Province, People's Republic of China
| | - Liangpu Xu
- Center for Prenatal Diagnosis, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, Fujian Province, People's Republic of China.,Fujian Key Laboratory for Prenatal Diagnosis and Birth Defects, Fuzhou 350001, Fujian Province, People's Republic of China
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Zhang H, Yue F, Zhang X, He J, Jiang Y, Liu R, Yu Y. Prenatal detection of distal 1q21.1q21.2 microduplication with abnormal ultrasound findings: Two cases report and literature review. Medicine (Baltimore) 2021; 100:e24227. [PMID: 33429818 PMCID: PMC7793324 DOI: 10.1097/md.0000000000024227] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 12/17/2020] [Indexed: 01/05/2023] Open
Abstract
RATIONALE 1q21.1 duplication is an uncommon chromosomal submicroscopic imbalance which is associated with growth/mental retardation, dysmorphic features, autism, multiple congenital and neuropsychiatric disorders. PATIENT CONCERNS Two pregnant women underwent amniocentesis for cytogenetic analysis and chromosomal microarray analysis (CMA) following abnormal ultrasound findings. Case 1 presented short nasal bone and case 2 showed absent nasal bone, ventricular septal defect and umbilical cord circling in ultrasonic examination. DIAGNOSES G-banding analysis showed that the two fetuses presented normal karyotypic results while CMA detected 1.796 Mb (case 1) and 1.242 Mb (case 2) microduplications in the region of 1q21.1q21.2 separately. Furthermore, the CMA also revealed a 1.2 Mb microdeletion of 8p23.3 in case 1. INTERVENTIONS The couple in case 1 chose to terminate the pregnancy, while the couple in case 2 continued the pregnancy and finally delivered a male infant who presented low nasal bridge and ventricular septal defect. OUTCOMES The 1q21.1q21.2 duplications in our report were located in the distal 1q21.1 region, overlapping with 1q21.1 duplication syndrome. Case 2 was the first reported live birth with 1q21.1 duplication according to prenatal CMA detection in China. LESSONS The genotype-phenotype of 1q21.1 duplication is complicated due to the phenotypic diversity, incomplete penetrance, and lack of obvious characteristics. So it is difficult to predict the postnatal development and health conditions clinically. Hence, long term follow up is necessary for newborn infants with 1q21.1 duplication, irrespective of whether the duplication is de novo or inherited.
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Affiliation(s)
- Hongguo Zhang
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital
- Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China
| | - Fagui Yue
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital
- Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China
| | - Xinyue Zhang
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital
- Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China
| | - Jing He
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital
- Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China
| | - Yuting Jiang
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital
- Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China
| | - Ruizhi Liu
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital
- Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China
| | - Yang Yu
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, First Hospital
- Jilin Engineering Research Center for Reproductive Medicine and Genetics, Jilin University, Changchun, China
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