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 DOI: 10.1002/humu.9482 2 de Brouwer et al.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 nonsyndromic and syndromic XLMR families with obligate female carriers.

Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1

“…First because, on the basis of observations by the EURO-MRX consortium, only B40% of the male patients (ie, here 54 out of 135) from small families can be assumed to carry a single gene defect on the X chromosome 13 and second because the frequencies of disease-causing mutations in the selected genes are each below a few percent. 1,14 The fact that we found an excess of missense mutations, as compared with protein-truncating mutations, is also in Whole-cell lysates from a control and a patient lymphoblastoid cell line that harbours a truncating mutation in PQBP1 (N143) were run in parallel on an SDS-PAGE gel.…”

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

“…Informed consent was obtained from the parents of the affected patients 9 and genomic DNA was isolated from peripheral blood according to standard procedures. DNA was dissolved in TE buffer at a concentration of 0.33 mg/ml and stored at 41C.…”

“…For the 401 individuals from affected male MR sibships and the 13 index patients from XLMR families, 9 the exon and splice site regions were PCR amplified (primer sequences and PCR conditions are available upon request) and submitted to denaturing high-performance liquid chromatography (DHPLC) analysis as previously described. 10 Sequencing reactions were then carried out for patient DNAs, which showed abnormal elution profiles in the DHPLC analysis.…”

“…17 The remaining seven XLMR families as well as the 401 male MR sibships were obtained through the EuroMRX Consortium (http://www.euromrx.com/); see also de Brouwer et al 9 Specific clinical information for the families where putatively causative changes in MCT8 were identified in this study is given below.…”

Novel deletion at Xq24 including the UBE2A gene in a patient with X-linked mental retardation

“…2,3 Each of these accounts for only a small number of families with XLMR and, despite this success, the genes involved in most affected families still await identification. 4 Recently, UBE2A/HR6A, one of the two human orthologs of Saccharomyces cerevisiae RAD6/UBC2 encoding E2 conjugase, was identified as causative of a novel XLMR syndrome through a nonsense mutation. 5 In the course of a program to screen possible patients with XLMR for copy-number aberrations by array-comparative genomic hybridization using a bacterial artificial chromosome (BAC)-based Xtilling array (MCG X-tilling array), 6 we detected a novel 0.4 Mb deletion at Xq24 that included UBE2A in a 4-year-old and 10-month-old boy with mental retardation.…”