Clinical and neurocognitive characterization of a family with a novel MED12 gene frameshift mutation.

FG syndrome, Lujan syndrome, and Ohdo syndrome, the Maat-Kievit-Brunner type, have been described as distinct syndromes with overlapping non-specific features and different missense mutations of the MED12 gene have been reported in all of them. We report a family including 10 males and 1 female affected with profound non-specific intellectual disability (ID) which was linked to a 30-cM region extending from Xp11.21 (ALAS2) to Xq22.3 (COL4A5). Parallel sequencing of all X-chromosome exons identified a frameshift mutation (c.5898dupC) of MED12. Mutated mRNA was not affected by non-sense mediated RNA decay and induced an additional abnormal isoform due to activation of cryptic splice-sites in exon 41. Dysmorphic features common to most affected males were long narrow face, high forehead, flat malar area, high nasal bridge, and short philtrum. Language was absent or very limited. Most patients had a friendly personality. Cognitive impairment, varying from borderline to profound ID was similarly observed in seven heterozygous females. There was no correlation between cognitive function and X-chromosome inactivation profiles in blood cells. The severe degree of ID in male patients, as well as variable cognitive impairment in heterozygous females suggests that the duplication observed in the present family may have a more severe effect on MED12 function than missense mutations. In a cognitively impaired male from this family, who also presented with tall stature and dysmorphism and did not have the MED12 mutation, a 600-kb duplication at 17p13.3 including the YWHAE gene, was found in a mosaic state.