MED12 Mutation in Two Families with X-Linked Ohdo Syndrome

Abstract

X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been shown to cause several forms of XLID, including Opitz-Kaveggia syndrome also known as FG syndrome (MIM #305450), Lujan-Fryns syndrome (MIM #309520) and the X-linked Ohdo syndrome (MIM #300895). Here, we report on two first cousins with X-linked Ohdo syndrome with a missense mutation in MED12 gene, identified through whole exome sequencing. The probands had facial features typical of X-linked Ohdo syndrome, including blepharophimosis, ptosis, a round face with a characteristic nose and a narrow mouth. Nextera DNA Exome kit (Illumina Inc., San Diego, CA, USA) was used for exome capture. The variant identified was a c.887G > A substitution in exon 7 of the MED12 gene leading to the substitution of a glutamine for a highly conserved arginine (p. Arg296Gln). Although the variant described has been previously reported in the literature, our study contributes to the expanding phenotypic spectrum of MED12-related disorders and above all, it demonstrates the phenotypic variability among different affected patients despite harboring identical mutations.

Keywords: MED12; X-linked intellectual deficiency; genotype-phenotype correlation; next generation sequencing (NGS).

Figure 1

Pedigree and photographs. (a) Pedigree of the two probands. Filled circles represent carrier females, unfilled squares represent unaffected males, filled squares represent affected males. Arrow indicates the probands. (b) Facial dysmorphisms of the two affected subjects (III-1 on the left, III-3 on the right) with facial features consistent with X-linked Ohdo syndrome: thin and arched eyebrows, blepharophimosis, ptosis, round face with a characteristic nose and a narrow mouth.

Figure 2

NGS data analyzed with IGV software and Sanger sequencing data analyzed with Chromas. (a) Photographs of IGV analysis reporting the c.887G > A, p.(R296Q) variant. Green line represents the variable base in IGV visualization (b) Sanger sequencing results of MED12 gene variant c.887G > A, p.(R296Q) in two affected individuals III-1, III-3 (hemizygous) and the unaffected mother II-3, II-4 (heterozygous). The site of the pathogenic variant is marked by a red line. (c) Alignment analysis of the amino acid sequences of MED12 from different species, showing complete conservation of the identified mutated residue (arrow).