Identification and characterization of genes in patients with severe mental retardation caused by autosomal dominant trait.

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Mental retardation (MR) is the most common cause of serious handicap in children and young adults. Defining features of MR include an IQ (intelligence quotient) of less than 70, together with associated functional deficits in adaptive behavior, which manifest themselves before 18 years of age. The molecular mechanisms underlying MR are quite heterogeneous and most of the genes responsible for MR are still unidentified. We have adopted the strategy of determining the chromosomal translocation breakpoints in two patients with profound mental retardation. Genes located at the translocation breakpoints should be candidates for MR and these conditions are likely caused by autosomal dominant traits. One patient (case 1 ) has a chromosomal translocation between 2q22 and 13q22 and the other (case 2) has 6q16 and 12p12. Case 1 has profound mental retardation, facial dysmorphism, microcephaly, delayed motor development, congenital heart disease and Hirschsprung disease, and was diagnosed as suffering from the Hirschsprung disease-Mental retardation (HSCR-MR) syndrome. The other patient has profound mental retardation and delayed motor development. We have identified ZFHX1B gene as a cause of the HSCR-MR syndrome, located at the 2q22 breakpoint. We also determined a translocation breakpoint on 6q16 from case 2. However our results suggest that the MR of case 2 is likely due to a defect in a gene located at 12p12.