Mutation Frequencies of X-linked Mental Retardation Genes in Families from the EuroMRX Consortium
ABSTRACT The EuroMRX family cohort consists of about 400 families with non-syndromic and 200 families with syndromic X-linked mental retardation (XLMR). After exclusion of Fragile X (Fra X) syndrome, probands from these families were tested for mutations in the coding sequence of 90 known and candidate XLMR genes. In total, 73 causative mutations were identified in 21 genes. For 42% of the families with obligate female carriers, the mental retardation phenotype could be explained by a mutation. There was no difference between families with (lod score >2) or without (lod score <2) significant linkage to the X chromosome. For families with two to five affected brothers (brother pair=BP families) only 17% of the MR could be explained. This is significantly lower (P=0.0067) than in families with obligate carrier females and indicates that the MR in about 40% (17/42) of the BP families is due to a single genetic defect on the X chromosome. The mutation frequency of XLMR genes in BP families is lower than can be expected on basis of the male to female ratio of patients with MR or observed recurrence risks. This might be explained by genetic risk factors on the X chromosome, resulting in a more complex etiology in a substantial portion of XLMR patients. The EuroMRX effort is the first attempt to unravel the molecular basis of cognitive dysfunction by large-scale approaches in a large patient cohort. Our results show that it is now possible to identify 42% of the genetic defects in non-syndromic and syndromic XLMR families with obligate female carriers. © 2007 Wiley-Liss, Inc.
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- "Three deletion and four duplication hotspots have been identified in XLIDcases [Gécz et al., 2009]. Moreover, X-exome sequencing has revealed a number of unique single nucleotide mutations in individual NS-XLID genes [de Brouwer et al., 2007; Tarpey et al., 2009], suggesting a high proportion of these variants in XLID families. "
ABSTRACT: X-linked intellectual disability (XLID) is a heterogeneous condition associated with mutations in >100 genes, accounting for over 10% of all cases of intellectual impairment. The majority of XLID cases show nonsyndromic forms (NSXLID), in which intellectual disability is the sole clinically consistent manifestation. Here we performed X chromosome exome (X-exome) sequencing to identify the causative mutation in an NSXLID family with four affected male siblings and five unaffected female siblings. The X-exome sequencing at 88× coverage in one affected male sibling revealed a novel missense mutation (p.Tyr1074Cys) in the asparagine-linked glycosylation 13 homolog (ALG13) gene. Segregation analysis by Sanger sequencing showed that the all affected siblings were hemizygous and the mother was heterozygous for the mutation. Recently, a de novo missense mutation in ALG13 has been reported in a patient with X-linked congenital disorders of glycosylation type I. Our study reports the first case of NSXLID caused by a mutation in ALG13 involved in protein N-glycosylation. © 2013 Wiley Periodicals, Inc.American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36233 · 2.05 Impact Factor
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- "Although none of the remaining 90 X-linked genes known today are responsible for such a large proportion of ID [Raymond, 2006; Tarpey et al., 2009], current practice for ID in males involves analysis of known XLID genes. Patients highly suggestive of having XLID include those with pedigrees involving intellectually disabled males from at least 2 different generations related to each other through carrier females (42% yield); those with similarly affected brothers (17% yield), and those with idiopathic ID in whom previous analyses for karyotype, subtelomeric rearrangements and FXS have revealed normal results (10% yield) [de Brouwer et al., 2007; Rogers et al., 2008]. XLID has been traditionally classified as syndromic or nonsyndromic; however, as with FXS, clinical conditions initially classified as nonsyndromic XLID may be subject to reclassification as syndromic XLID, following revision of clinical experience and molecular data [Madrigal et al., 2007a; Nawara et al., 2008; Vandewalle et al., 2009; Fusco et al., 2010]. "
ABSTRACT: Intellectual disability (ID) has a prevalence of 2-3% with 0.3% of the population being severely retarded. Etiology is heterogeneous, owing to numerous genetic and environmental factors. Underlying etiology remains undetermined in 75-80% of mildly disabled patients and 20-50% of those severely disabled. Twelve percent of all ID is thought to be X-linked (XLID). This study covers copy number analysis of some of the known XLID genes, using multiplex ligation-dependent probe amplification (MLPA) in 100 nonsyndromic patients. One of the patients was found to have duplication in all exons of MECP2 gene, and another had duplication in the fifth exon of TM4SF2/TSPAN7 gene. Affymetrix® 6.0 whole-genome SNP microarray confirmed the duplication in MECP2 and showed duplication of exons 2-7 in TM4SF2/TSPAN7, respectively. MECP2 duplication has recently been recognized as a syndromic cause of XLID in males, whereas duplications in TM4SF2/TSPAN7 are yet to be determined as a cause of XLID. Being an efficient, rapid, easy-to-perform, easy-to-interpret, and cost-effective method of copy number analysis of specific DNA sequences, MLPA presents wide clinical utility and may be included in diagnostic workup of ID, particularly when microarrays are unavailable as a first-line approach.Molecular syndromology 01/2012; 2(2):64-71. DOI:10.1159/000334289
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- "There is 30–50% excess of males with MR compared to females [Leonard and Wen, 2002], which suggested that X-chromosomal mutations could account for up to 25% of males with MR [Herbst and Miller, 1980]. This estimate has been adjusted to $10% based on the frequency of mutations in known X-linked MR (XLMR) genes in males with MR [Mandel and Chelly, 2004; de Brouwer et al., 2007]. This lower frequency of X-chromosomal gene mutations in patients with MR has led to the hypothesis that common X-chromosomal variants could affect cognitive abilities and account for part of the male MR excess [Mandel and Chelly, 2004]. "
ABSTRACT: ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation.American Journal of Medical Genetics Part A 03/2010; 152A(3):638-45. DOI:10.1002/ajmg.a.33292 · 2.05 Impact Factor