ASSOCIATION OF AN X-CHROMOSOME DODECAMER INSERTIONAL VARIANT ALLELE WITH MENTAL-RETARDATION

Mental retardation is a prominent feature of many neurodevelopmental s yndromes. In an attempt to identify genetic components of these illnes ses, we isolated and sequenced a large number of human genomic cosmid inserts containing large trinucleotide repeats. One of these cosmids, Cos-4, maps to the X-chromosome and contains the sequence of a 7.3-kb mRNA. Initial polymorphism analysis across a region of repetitive DNA in this gene revealed a rare 12-bp exonic variation (<<1% in non-ill m ales) having an increased prevalence in non-fragile X males with menta l retardation (4%, P < 0.04, n = 81). This variant was not present in the highly conserved mouse homologue that has 100% amino acid identity to the human sequence near the polymorphism. Subsequent screening of two additional independent cohorts of non-fragile X mentally retarded patients and ethnically matched controls demonstrated an even higher p revalence of the 12-bp variant in males with mental retardation (8%, P < 0.0003, n = 125, and 14%, P < 0.10, n = 36) vs the controls. Multiv ariate analysis was conducted in an effort to identify other phenotypi c components in affected individuals, and the findings suggested an in creased incidence of histories of hypothyroidism (P < 0.001) and treat ment with antidepressants (P < 0.001). We conclude that the presence o f this 12-bp variant confers significant susceptibility for mental ret ardation.