IDENTIFICATION OF GENETIC DEFECTS IN X-LINKED MENTAL RETARDATION

Abstract

Backgrounds: X-linked mental retardation (XLMR) has been the focus of MR research because of 40% excess of males with MR. Genetic defects are estimated to account for 50% MR cases. There are still 56 non-syndromic (MRX) and 35 syndromic XLMR (MRXS) loci with unknown causative genes. Aims: Identification of the genetic defects in XLMR families. Methods: Four MRXS and 6 MRX families were studied. Clinical dysmorphologic examination and conventional cytogenetic analysis were performed followed by Fragile- X exclusion. Linkage analysis was conducted with highly polymorphic STR-markers on the X-chromosome followed by LOD scores calculation. An FMR1 X-inactivation assay was performed in 15 females from all families, followed by AR method if the result were uninformative for FMR1. Candidate genes were selected in linkage interval and mutation analysis was performed. Results: Gross numerical chromosomal abnormalities and Fragile-X were excluded in all 10 families. Ten XLMR families showed intervals varying from 20 Mb to 121 Mb. Family W92-053 (mental retardation and hypomyelination) showed no mutation in HSD17B10, UBQLN2, SYP, ARGHEF. Two families with MR and congenital hydrocephalus (P03-0452 and 13753/HC) showed no mutations in SLITRK2 and SLITRK4. Family DF27004 (MR and overgrowth features) showed no mutations in GPC3. Family W092-053, PO3-0452, DF27004, and W08-2152 showed skewed Xinactivation in the obligate carrier female. Conclusions: Genetic defects identification in ten families showed varying linkage intervals from 20 Mb to 121 Mb with varying LOD scores from 0,17 to 3.3, skewed Xinactivation in 4 families, and no mutation in the candidate genes. STR markers analysis was useful in determining linkage intervals, narrowing down the region of interest for further studies, and genetic counselling. Keywords: X-linked mental retardation, genetic defects, linkage analysis, mutation analysis