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Tolmacheva EN, Fonova EA, Lebedev IN. X-Linked CNV in Pathogenetics of Intellectual Disability. RUSS J GENET+ 2022; 58:1193-1207. [DOI: 10.1134/s102279542210009x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/25/2022] [Accepted: 05/31/2022] [Indexed: 01/05/2025]
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2
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Shakarami F, Jahani M, Nouri Z, Tabatabaiefar MA. X-linked mental retardation-hypotonic facies syndrome: Exome sequencing identifies novel clinical characteristics associated with c.5182G>C mutation in the ATRX gene. Mol Genet Genomic Med 2022; 10:e2034. [PMID: 35962714 PMCID: PMC9544208 DOI: 10.1002/mgg3.2034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 07/15/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Background X‐linked mental retardation‐hypotonic facies syndrome‐1 (MRXFH1), caused by a mutation in the ATRX gene, is a rare syndromic form of X‐linked mental retardation (XLMR) that is mainly characterized by severe intellectual disability, dysmorphic facies, and skewed X‐inactivation pattern in carrier women. Method In this study, due to the genetic heterogeneity of the disease, we performed exome sequencing (ES) on a 15‐year‐old boy with primary microcephaly and intellectual disability. Also, Sanger sequencing, cosegregation analysis, and structural modeling were done to identify and verify the causative variant in the proband and other affected individuals in the family. In addition, we collected data from previously reported cases to compare with our patients' phenotypes. Results ES revealed a previously reported missense variant in the ATRX gene (c.5182G > C, p.Ala1728Pro), segregating with the new clinical characteristic including primary microcephaly in the pedigree. This variant meets the criteria of being likely pathogenic based on the ACMG variant interpretation guideline. Conclusions The findings of this study extend the spectrum of phenotypes associated with the identified variant and provide further details on its clinical features.
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Affiliation(s)
- Fatemeh Shakarami
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehdi Jahani
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Zahra Nouri
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Genetics Department, Erythron Pathobiology and Genetics Lab, Isfahan, Iran
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.,GenTArget Corp (GTAC), Deputy of Research and Technology, Isfahan University of Medical Sciences, Isfahan, Iran
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3
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Li L, Yu J, Zhang X, Han M, Liu W, Li H, Liu S. A novel ATRX mutation causes Smith‑Fineman‑Myers syndrome in a Chinese family. Mol Med Rep 2019; 21:387-392. [PMID: 31746429 DOI: 10.3892/mmr.2019.10818] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Accepted: 09/30/2019] [Indexed: 11/06/2022] Open
Abstract
Smith‑Fineman‑Myers syndrome (SFMS) is a rare inherited disorder characterized mainly by mental retardation and anomalies in the appearance of patients. SFMS is caused by a mutation in the α‑thalassemia/mental retardation syndrome X‑linked (ATRX) gene and has an X‑linked recessive pattern. In the present study, a novel ATRX mutation was identified, and the association between its genotype and the phenotype was explored in a Chinese Han family with SFMS. This study aimed to lay a foundation for prenatal diagnosis for this family. Briefly, genomic DNA was extracted from peripheral blood samples obtained from the family. High‑throughput genetic sequencing was employed to detect the whole exome; subsequently, Sanger sequencing was performed to verify the candidate mutations. Clinical analysis of the proband was also accomplished. Consequently, a novel missense ATRX mutation was identified comprising a single nucleotide change of C to T, which caused an amino acid substitution at codon 172 in exon 7 (c.515C>T; p.Thr172Ile) of the proband. This mutation was found to co‑segregate in the present SFMS pedigree and was located in a highly conserved region of the ATRX protein, thus suggesting that it may be a pathogenic mutation. Taken together, these findings provided novel information that may lead towards an improved understanding of the genetic and clinical features of patients with SFMS, thereby facilitating a more accurate prenatal diagnosis of SFMS.
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Affiliation(s)
- Liangshan Li
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Jing Yu
- Department of Clinical Laboratory, Medical College of Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xiao Zhang
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Mengmeng Han
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Wenmiao Liu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Hui Li
- Health Physical Examination Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Shiguo Liu
- Medical Genetic Department, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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Riveiro AR, Mariani L, Malmberg E, Amendola PG, Peltonen J, Wong G, Salcini AE. JMJD-1.2/PHF8 controls axon guidance by regulating Hedgehog-like signaling. Development 2017; 144:856-865. [PMID: 28126843 DOI: 10.1242/dev.142695] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 01/09/2017] [Indexed: 01/10/2023]
Abstract
Components of the KDM7 family of histone demethylases are implicated in neuronal development and one member, PHF8, is often found to be mutated in cases of X-linked mental retardation. However, how PHF8 regulates neurodevelopmental processes and contributes to the disease is still largely unknown. Here, we show that the catalytic activity of a PHF8 homolog in Caenorhabditis elegans, JMJD-1.2, is required non-cell-autonomously for proper axon guidance. Loss of JMJD-1.2 dysregulates transcription of the Hedgehog-related genes wrt-8 and grl-16, the overexpression of which is sufficient to induce the axonal defects. Deficiency of either wrt-8 or grl-16, or reduced expression of homologs of genes promoting Hedgehog signaling, restores correct axon guidance in jmjd-1.2 mutants. Genetic and overexpression data indicate that Hedgehog-related genes act on axon guidance through actin remodelers. Thus, our study highlights a novel function of jmjd-1.2 in axon guidance that might be relevant for the onset of X-linked mental retardation and provides compelling evidence of a conserved function of the Hedgehog pathway in C. elegans axon migration.
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Affiliation(s)
- Alba Redo Riveiro
- Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen, Denmark.,Centre for Epigenetics, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Luca Mariani
- Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen, Denmark.,Centre for Epigenetics, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Emily Malmberg
- Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen, Denmark.,Centre for Epigenetics, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Pier Giorgio Amendola
- Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen, Denmark.,Centre for Epigenetics, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Juhani Peltonen
- A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, 70211, Kuopio, Finland
| | - Garry Wong
- Faculty of Health Sciences, University of Macau, 999078, Macau, China
| | - Anna Elisabetta Salcini
- Biotech Research & Innovation Centre (BRIC), University of Copenhagen, 2200, Copenhagen, Denmark .,Centre for Epigenetics, University of Copenhagen, 2200, Copenhagen, Denmark
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5
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Mundhofir FEP, Winarni TI, Nillesen W, Bon BWMV, Schepens M, Ruiterkamp-Versteeg M, Hamel BCJ, Yntema HG, Faradz SMH. Prevalence of fragile X syndrome in males and females in Indonesia. World J Med Genet 2012; 2:15-22. [DOI: 10.5496/wjmg.v2.i3.15] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the prevalence of fragile X syndrome (FXS) in intellectually disabled male and female Indonesians.
METHODS: This research is an extension of a previously reported study on the identification of chromosomal aberrations in a large cohort of 527 Indonesians with intellectual disability (ID). In this previous study, 87 patients had a chromosomal abnormality, five of whom expressed fragile sites on Xq27.3. Since FXS cannot always be identified by cytogenetic analysis, molecular testing of the fragile X mental retardation 1 CGG repeat was performed in 440 samples. The testing was also conducted in the five previously identified samples to confirm the abnormality. In total, a molecular study was conducted in 445 samples (162 females and 283 males).
RESULTS: In the cohort of Indonesian ID population, the prevalence of FXS is 9/527 (1.7%). The prevalence in males and females is 1.5% (5/329) and 2% (4/198), respectively. Segregation analysis in the families and X-inactivation studies were performed. We performed the first comprehensive genetic survey of a representative sample of male and female ID individuals from institutions and special schools in Indonesia. Our findings show that a comprehensive study of FXS can be performed in a developing country like Indonesia where diagnostic facilities are limited.
CONCLUSION: The prevalence of FXS is equal in females and males in our study, which suggests that the prevalence of FXS in females could be underestimated.
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Soltani Banavandi MJ, Kahrizi K, Behjati F, Mohseni M, Darvish H, Bahman I, Abedinni SS, Ghasemi Firouzabadi S, Jafari E, Ghadami S, Sabbagh F, Kavoosi GR, Najmabadi H. Investigation of genetic causes of intellectual disability in kerman province, South East of iran. IRANIAN RED CRESCENT MEDICAL JOURNAL 2012; 14:79-85. [PMID: 22737560 PMCID: PMC3372047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2011] [Accepted: 10/12/2011] [Indexed: 11/30/2022]
Abstract
BACKGROUND Intellectual disability (ID) has a worldwide prevalence of 1-3% and results from extraordinary heterogeneous. To shed more light on the causes of ID in Kerman Province, in Southeast Iran, we set out in 2008 to perform systematic clinical studies and homozygosity mapping in large Iranian families with ID. METHODS Fifty seven families with a minimum of two mentally retarded children from Kerman Province were initially tested for metabolic disorders, by Tandem mass spectrometry. Fragile X testing and standard karyotyping were performed for all probands of families. Cases with autosomal recessive (AR) pattern of inheritance and microcephaly were subjected to homozygosity mapping by using several microsatellite markers for known MCPH loci. RESULTS Three out of seven families with X-linked pattern of inheritance were positive for fragile X syndrome. Chromosome abnormality was not observed in any of dysmorphic patients and all families were negative for metabolic tests. Among the remaining 50 families of AR ID, six were found to be microcephalic, of which 2 linked to two MCPH loci (33.3%). The rest 4 families were not linked to any of the known loci. CONCLUSION The results of this study showed that ID with microcephaly comprised 12% of ID cases in Kerman Province. In two families with apparent linkage to the MCPH5 and MCPH6 locus, mutation screening was not successful, which might indicate that either the mutation is located in the regulatory sequences of the gene or that there might be another genes present in these regions, which is mutated in such cases.
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Affiliation(s)
- M J Soltani Banavandi
- Faculty of Basic Science, Science and Research Branch, Islamic Azad University, Fars, Iran,Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - K Kahrizi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - F Behjati
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - M Mohseni
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - H Darvish
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - I Bahman
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - S S Abedinni
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - S Ghasemi Firouzabadi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - E Jafari
- Deptartment of Microbiology, Faculty of Basic Science, Islamic Azad University, Kerman Branch, Kerman, Iran
| | - Sh Ghadami
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - F Sabbagh
- Genetics Counseling Center, Welfare Organization of Kerman Province, Kerman, Iran
| | - Gh R Kavoosi
- Institute of Biotechnology, University of Shiraz, Shiraz, Iran
| | - H Najmabadi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran,Correspondence: Hossein Najmabadi, PhD, Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Tel.: +98-21-22180138, Fax: +98-21-22180138, E-mail:
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Indhumathi N, Singh D, Chong SS, Thelma BK, Arabandi R, Srisailpathy CRS. Fragile X CGG repeat variation in Tamil Nadu, South India: a comparison of radioactive and methylation-specific polymerase chain reaction in CGG repeat sizing. Genet Test Mol Biomarkers 2011; 16:113-22. [PMID: 22023245 DOI: 10.1089/gtmb.2011.0102] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Fragile X syndrome is the most frequent hereditary cause of mental retardation after Down syndrome. Expansion of CGG repeats in the 5' UTR of the fragile X mental retardation gene 1 (FMR1) causes gene inactivation in most of the cases. The FMR1 gene is classified into normal 5-44; gray zone 45-54; premutation 55 to <200; and full mutation ≥ 00 repeats. Precise sizing of FMR1 alleles is important to understand their variation, predisposition, and for genetic counseling. Meta-analysis reveals prevalence of premutation carriers as 1 in 259. No such reports are available in India. About 705 women from Tamil Nadu, South India, were screened for the FMR1 allelic variation by using radioactive polymerase chain reaction-polyacrylamide gel electrophoresis (PAGE) analysis. The women who were homozygous by radioactive polymerase chain reaction (rPCR) were reanalyzed by methylation-specific polymerase chain reaction (Ms-PCR) and GeneScan analysis. The techniques were validated and compared to arrive at a correction factor. Among 122 genotypes, 35 repeat variants ranging in size from 16 to 57 were observed. The most common repeat is 30 followed by 29. One in 353 women carried the premutation. No full mutations were observed. Screening populations with low frequency of premutations may not be applicable. Ms-PCR is more suitable for routine screening and clinical testing compared with rPCR-PAGE analysis.
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Affiliation(s)
- Nagarathinam Indhumathi
- Department of Genetics, Dr. A. Lakshmanaswami Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, India
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8
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Moraine C, Bonnet-Brilhault F, Laumonnier F, Gomot M. Could autism with mental retardation result from digenism and frequent de novo mutations? World J Biol Psychiatry 2010; 10:1030-6. [PMID: 19160128 DOI: 10.1080/15622970802627455] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The high concordance for autism symptoms in monozygotic twin-pairs compared to di-zygotic twins and/or non-twin sib-ships suggests a high genetic determinism in autism. Those results have hypothesized multi-factorial determinism in accordance with family studies and mathematical models. However, linkage and association or candidate gene strategies have failed to-date to identify clearly involved mechanisms. Mental retardation (MR) is known as frequently associated to autism. Multiplex XLMR pedigrees have been reported with only one mutated patient having autism and MR: different X-located MR genes have been shown to be involved (NLGN4, MECP2, OPHN1, ZNF674 and FRAXA) which does not suggest that they could be "autism genes". Tuberous sclerosis studies and report of numerous autosomal domains shown deleted in MR-autistic subjects suggest that several autosomal dominant (AD) genes could be also involved in MR with autism. Whereas multiplex AD-MR families are rare, AD de novo mutations could explain numerous sporadic situations of non-specific MR and of autism with MR, in accordance with twin studies. Finally, we hypothesize that in those autistic subjects with mendelian MR, the XL-MR or AD-MR gene (G1) would pave the way for a second Mendelian factor (G2) responsible for autism symptoms.
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Crespi B, Summers K, Dorus S. Evolutionary genomics of human intellectual disability. Evol Appl 2010; 3:52-63. [PMID: 25567903 PMCID: PMC3352458 DOI: 10.1111/j.1752-4571.2009.00098.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2009] [Accepted: 07/28/2009] [Indexed: 01/28/2023] Open
Abstract
Previous studies have postulated that X-linked and autosomal genes underlying human intellectual disability may have also mediated the evolution of human cognition. We have conducted the first comprehensive assessment of the extent and patterns of positive Darwinian selection on intellectual disability genes in humans. We report three main findings. First, as noted in some previous reports, intellectual disability genes with primary functions in the central nervous system exhibit a significant concentration to the X chromosome. Second, there was no evidence for a higher incidence of recent positive selection on X-linked than autosomal intellectual disability genes, nor was there a higher incidence of selection on such genes overall, compared to sets of control genes. However, the X-linked intellectual disability genes inferred to be subject to recent positive selection were concentrated in the Rho GTP-ase pathway, a key signaling pathway in neural development and function. Third, among all intellectual disability genes, there was evidence for a higher incidence of recent positive selection on genes involved in DNA repair, but not for genes involved in other functions. These results provide evidence that alterations to genes in the Rho GTP-ase and DNA-repair pathways may play especially-important roles in the evolution of human cognition and vulnerability to genetically-based intellectual disability.
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Affiliation(s)
- Bernard Crespi
- Department of Biosciences, Simon Fraser UniversityBurnaby, BC, Canada
| | - Kyle Summers
- Department of Biology, East Carolina UniversityGreenville, NC, USA
| | - Steve Dorus
- Department of Biology and Biochemistry, University of BathBath, UK
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Bashiardes S, Kousoulidou L, van Bokhoven H, Ropers HH, Chelly J, Moraine C, de Brouwer APM, Van Esch H, Froyen G, Patsalis PC. A new chromosome x exon-specific microarray platform for screening of patients with X-linked disorders. J Mol Diagn 2009; 11:562-8. [PMID: 19779134 DOI: 10.2353/jmoldx.2009.090086] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Recent studies and advances in high-density oligonucleotide arrays have shown that microdeletions and microduplications occur at a high frequency in the human genome, causing various genetic conditions including mental retardation. Thus far little is known about the pathways leading to this disease, and implementation of microarrays is hampered by their increasing cost and complexity, underlining the need for new diagnostic tools. The aim of this study was to introduce a new targeted platform called "chromosome X exon-specific array" and to apply this new platform to screening of 20 families (including one blind positive control) with suspected X-linked mental retardation, to identify new causative X-linked mental retardation genes. The new microarray contains of 21,939 oligonucleotides covering 92.9% of all exons of all genes on chromosome X. Patient screening resulted in successful identification of the blind positive control included in the sample of 20 families, and one of the remaining 19 families was found to carry a 1.78-kilobase deletion involving all exons of pseudogene BRAF2. The BRAF2 deletion segregated in the family and was not found in 200 normal male samples, and no copy number variations are reported in this region. Further studies and focused investigation of X-linked disorders have the potential to reveal the molecular basis of human genetic pathological conditions that are caused by copy-number changes in chromosome X genes.
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Affiliation(s)
- Stavros Bashiardes
- Cyprus Institute of Neurology and Genetics, PO Box 23462, 1683 Nicosia, Cyprus
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Pouya AR, Abedini SS, Mansoorian N, Behjati F, Nikzat N, Mohseni M, Nieh SE, Abbasi Moheb L, Darvish H, Monajemi GB, Banihashemi S, Kahrizi K, Ropers HH, Najmabadi H. Fragile X syndrome screening of families with consanguineous and non-consanguineous parents in the Iranian population. Eur J Med Genet 2009; 52:170-3. [PMID: 19361583 DOI: 10.1016/j.ejmg.2009.03.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2008] [Accepted: 03/27/2009] [Indexed: 11/20/2022]
Abstract
Fragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentally retarded males, the frequency of fragile X syndrome is approximately 2-3 percent, but little is known about its proportion in mentally retarded patients from countries where parental consanguinity is common. The objective of this study was to estimate the frequency of fragile X syndrome (FXS) in mentally retarded patients from Iran. We examined a total of 508 families with MR that had been referred to the Genetics Research Center (GRC) in Tehran of which 467 families had at least two mentally retarded children. In 384 families, the parents were related and in 124 they were not related of which most of them had putative or established X-linked inheritance pattern. Full FMR1 mutations were found in 32 of the 508 families studied (6.3%), in 19 out of 124 families with apparently unrelated parents (15.3%), and in 13 of the 384 consanguineous families (3.4%). Thus, in Iran, the relative frequency of FXS seems to be high, and in patients with unrelated parents is much higher. We also show that even in families with consanguineous parents, FXS has to be ruled out before assuming that familial MR is due to autosomal recessive gene defects. Molecular studies are in progress to explain the high proportion of FMR1 mutations in mentally retarded offspring of unrelated Iranian parents.
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Affiliation(s)
- Ali Reza Pouya
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
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[X-linked West syndrome]. An Pediatr (Barc) 2009; 70:85-8. [PMID: 19174126 DOI: 10.1016/j.anpedi.2008.08.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2008] [Revised: 07/31/2008] [Accepted: 08/01/2008] [Indexed: 11/22/2022] Open
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13
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Bedeschi MF, Novelli A, Bernardini L, Parazzini C, Bianchi V, Torres B, Natacci F, Giuffrida MG, Ficarazzi P, Dallapiccola B, Lalatta F. Association of syndromic mental retardation with an Xq12q13.1 duplication encompassing the oligophrenin 1 gene. Am J Med Genet A 2008; 146A:1718-24. [PMID: 18512229 DOI: 10.1002/ajmg.a.32365] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OPHN1 mutations cause a syndromic form of mental retardation (MR) characterized by cerebellar hypoplasia, early hypotonia, motor and speech delay, with occasional seizures and strabismus. Here we report on a familial chromosome duplication spanning about 800 Kb of Xq12q13.1, associated with MR and a distinctive phenotype in the affected male, but not in his heterozygous mother. The parents were healthy and non-consanguineous with a history of three pregnancies. The first resulted in the birth of a boy with MR, motor impairment and seizures. The second pregnancy was terminated because of trisomy 18. At the time of the third, the first affected boy was analyzed by array-CGH, which revealed a 800 Kb duplication at Xq12q13.1, encompassing three genes, including OPHN1. This mutation was inherited from his healthy mother and was not present in any of the three maternal brothers. To our knowledge this is the first report of a clinical phenotype associated with duplication of Xq12q13.
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Affiliation(s)
- Maria Francesca Bedeschi
- Clinical Genetics Unit, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy.
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Aitken KJ. Intersubjectivity, affective neuroscience, and the neurobiology of autistic spectrum disorders: a systematic review. Keio J Med 2008; 57:15-36. [PMID: 18382122 DOI: 10.2302/kjm.57.15] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Intersubjectivity is an approach to the study of social interaction viewed from a perspective which rejects the view that reducing any such analysis to study at the level of the individual is adequate to address the issues of social functioning. It also stresses the view that social processes cannot be reduced to cognitive ones - most of the important questions in the study of developmental psychopathology deal with issues which have commonality with many other species and are patent well before the ontological emergence of 'cognitive' abilities. In this paper we review the evidence in this area, and discuss a range of issues relevant to autistic spectrum disorders. We focus in particular on social interaction; the role of the Intrinsic Motive Formation and recent work on mirror neurons in autism; genetic and teratogenic factors in the genesis of autism; and the role of a number of biological factors in pathogenesis - tryptophan; vitamin B12; sterol metabolism; glutamate and GABA; and the Fragile-X expansion.
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Abstract
X-linked mental retardation (XLMR) is a common cause of inherited intellectual disability with an estimated prevalence of approximately 1/1000 males. Most XLMR conditions are inherited as X-linked recessive traits, although female carriers may manifest usually milder symptoms. We have listed 215 XLMR conditions, subdivided according to their clinical presentation: 149 with specific clinical findings, including 98 syndromes and 51 neuromuscular conditions, and 66 nonspecific (MRX) forms. We also present a map of the 82 XLMR genes cloned to date (November 2007) and a map of the 97 conditions that have been positioned by linkage analysis or cytogenetic breakpoints. We briefly consider the molecular function of known XLMR proteins and discuss the possible strategies to identify the remaining XLMR genes. Final remarks are made on the natural history of XLMR conditions and on diagnostic issues.
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Affiliation(s)
- Pietro Chiurazzi
- Institute of Medical Genetics, Catholic University, Rome, Italy.
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16
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Kousoulidou L, Parkel S, Zilina O, Palta P, Puusepp H, Remm M, Turner G, Boyle J, van Bokhoven H, de Brouwer A, Van Esch H, Froyen G, Ropers HH, Chelly J, Moraine C, Gecz J, Kurg A, Patsalis PC. Screening of 20 patients with X-linked mental retardation using chromosome X-specific array-MAPH. Eur J Med Genet 2007; 50:399-410. [DOI: 10.1016/j.ejmg.2007.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2007] [Accepted: 09/23/2007] [Indexed: 02/04/2023]
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Abstract
Fragile X syndrome is the most common form of inherited mental retardation. The disorder is mainly caused by the expansion of the trinucleotide sequence CGG located in the 5' UTR of the FMR1 gene on the X chromosome. The abnormal expansion of this triplet leads to hypermethylation and consequent silencing of the FMR1 gene. Thus, the absence of the encoded protein (FMRP) is the basis for the phenotype. FMRP is a selective RNA-binding protein that associates with polyribosomes and acts as a negative regulator of translation. FMRP appears to play an important role in synaptic plasticity by regulating the synthesis of proteins encoded by certain mRNAs localized in the dendrite. An advancing understanding of the pathophysiology of this disorder has led to promising strategies for pharmacologic interventions.
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Affiliation(s)
- Olga Penagarikano
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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18
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Laperuta C, Spizzichino L, D'Adamo P, Monfregola J, Maiorino A, D'Eustacchio A, Ventruto V, Neri G, D'Urso M, Chiurazzi P, Ursini MV, Miano MG. MRX87 family with Aristaless X dup24bp mutation and implication for polyAlanine expansions. BMC MEDICAL GENETICS 2007; 8:25. [PMID: 17480217 PMCID: PMC1868705 DOI: 10.1186/1471-2350-8-25] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2006] [Accepted: 05/04/2007] [Indexed: 12/02/2022]
Abstract
Background Cognitive impairments are heterogeneous conditions, and it is estimated that 10% may be caused by a defect of mental function genes on the X chromosome. One of those genes is Aristaless related homeobox (ARX) encoding a polyA-rich homeobox transcription factor essential for cerebral patterning and its mutations cause different neurologic disorders. We reported on the clinical and genetic analysis of an Italian family with X-linked mental retardation (XLMR) and intra-familial heterogeneity, and provided insight into its molecular defect. Methods We carried out on linkage-candidate gene studies in a new MRX family (MRX87). All coding regions and exon-intron boundaries of ARX gene were analysed by direct sequencing. Results MRX87 patients had moderate to profound cognition impairment and a combination of minor congenital anomalies. The disease locus, MRX87, was mapped between DXS7104 and DXS1214, placing it in Xp22-p21 interval, a hot spot region for mental handicap. An in frame duplication of 24 bp (ARXdup24) in the second polyAlanine tract (polyA_II) in ARX was identified. Conclusion Our study underlines the role of ARXdup24 as a critical mutational site causing mental retardation linked to Xp22. Phenotypic heterogeneity of MRX87 patients represents a new observation relevant to the functional consequences of polyAlanine expansions enriching the puzzling complexity of ARXdup24-linked diseases.
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Affiliation(s)
- Carmela Laperuta
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso" CNR, Naples, Italy
| | | | - Pio D'Adamo
- Telethon Institute of Genetics and Medicine, TIGEM, Naples, Italy
| | - Jlenia Monfregola
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso" CNR, Naples, Italy
| | | | | | - Valerio Ventruto
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso" CNR, Naples, Italy
| | | | - Michele D'Urso
- Institute of Genetics and Biophysics "Adriano Buzzati Traverso" CNR, Naples, Italy
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19
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Chelly J, Khelfaoui M, Francis F, Chérif B, Bienvenu T. Genetics and pathophysiology of mental retardation. Eur J Hum Genet 2006; 14:701-13. [PMID: 16721406 DOI: 10.1038/sj.ejhg.5201595] [Citation(s) in RCA: 188] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/08/2022] Open
Abstract
Mental retardation (MR) is defined as an overall intelligence quotient lower than 70, associated with functional deficit in adaptive behavior, such as daily-living skills, social skills and communication. Affecting 1-3% of the population and resulting from extraordinary heterogeneous environmental, chromosomal and monogenic causes, MR represents one of the most difficult challenges faced today by clinician and geneticists. Detailed analysis of the Online Mendelian Inheritance in Man database and literature searches revealed more than a thousand entries for MR, and more than 290 genes involved in clinical phenotypes or syndromes, metabolic or neurological disorders characterized by MR. We estimate that many more MR genes remain to be identified. The purpose of this review is to provide an overview on the remarkable progress achieved over the last decade in delineating genetic causes of MR, and to highlight the emerging biological and cellular processes and pathways underlying pathogeneses of human cognitive disorders.
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Affiliation(s)
- Jamel Chelly
- Institut Cochin, Inserm-U567, CNRS-UMR 8104, Université Paris 5 René Descartes, Faculté de Médecine René Descartes, Paris, France.
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Tabolacci E, Pomponi MG, Pietrobono R, Terracciano A, Chiurazzi P, Neri G. A truncating mutation in the IL1RAPL1 gene is responsible for X-linked mental retardation in the MRX21 family. Am J Med Genet A 2006; 140:482-7. [PMID: 16470793 DOI: 10.1002/ajmg.a.31107] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
X-linked mental retardation (XLMR) is a genetically heterogeneous condition, due to mutations in at least 50 genes, involved in functioning of the central nervous system and located on the X chromosome. Nonspecific XLMR (MRX) is characterized essentially by mental retardation transmitted by X-linked inheritance. More than 80 extended MRX pedigrees have been reported to date, which have been distinguished exclusively by physical position of the corresponding gene on the X chromosome, established by linkage analysis. One such family, MRX21, which was described by us in 1993 and localized to Xp11.4-pter, has now been reanalyzed with additional markers and after one more affected individual had became available. This extra information allowed a significant reduction of the linkage interval and, eventually, identification of the mutant gene. A stop mutation in exon 10 of the IL1RAPL1 gene (in Xp21) was found in the four affected males and in obligate carriers, allowing conclusive counseling of other family members of uncertain carrier status. The W487X mutation results in the production of a truncated IL1RAPL protein, comprised of the extracellular Ig-like domain and transmembrane tract, but lacking the last 210 aminoacids of the cytoplasmic domain. MRX21 is the first extended MRX family with a point mutation in IL1RAPL1 and the second with a stop mutation, which had been previously found only in a small family. Our report confirms the role of the IL1RAPL1 gene in causing nonspecific mental retardation in males and underlines the importance of detailed linkage analysis before candidate gene mutational screening.
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Nawara M, Szczaluba K, Poirier K, Chrzanowska K, Pilch J, Bal J, Chelly J, Mazurczak T. TheARX mutations: A frequent cause of X-linked mental retardation. Am J Med Genet A 2006; 140:727-32. [PMID: 16523516 DOI: 10.1002/ajmg.a.31151] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The ARX gene mutations have been demonstrated to cause different forms of mental retardation (MR). Beside FMR1, in families with X-linked mental retardation (XLMR), the ARX dysfunction was demonstrated to be among the most frequent causes of this heterogeneous group of disorders. Nevertheless, in sporadic cases of MR, ARX mutations are extremely rare. In order to evaluate the frequency of ARX mutation in XLMR, we performed mutational analysis of ARX in 165 mentally retarded probands negative for FRAXA and belonging to families in which the condition segregates as an X-linked condition. The same recurrent mutation, an in frame 24 bp insertion (c.428-451 dup (24 bp)), was identified in five patients. In one family, the mother of two affected boys was found not to carry the mutation detected in her sons. These data suggest the presence of germline mosaicism for the mutation in the mother. Our results confirm the significant contribution of ARX mutations in the etiology of MR, especially in this group of patients selected for XLMR (3%). These data, together with those reported in the literature, imply that screening for c.428-451 dup (24 bp) mutation should be recommended in all patients with suspected XLMR.
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Affiliation(s)
- Magdalena Nawara
- Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17a, Warsaw, Poland.
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Tabolacci E, Zollino M, Lecce R, Sangiorgi E, Gurrieri F, Leuzzi V, Opitz JM, Neri G. Two brothers with 22q13 deletion syndrome and features suggestive of the Clark???Baraitser syndrome. Clin Dysmorphol 2005. [DOI: 10.1097/00019605-200507000-00004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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