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

Abstract

FG syndrome, Lujan syndrome, and Ohdo syndrome, the MaatKievit-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.

Redefining the MED13L syndrome

“…4 Although in these cases, the individual effect of increased MED13L dosage cannot be determined because of the involvement of several genes, it further underlines a possible gene dosage effect. MED13L is only one component of the mediator complex linked to human disease: (i) MED12 gene variants cause Lujan-Fryns syndrome (MIM #309520), 25 Ohdo syndrome (MIM #300895), 26 Opitz-Kaveggia syndrome (MIM #305450), 27 and profound ID that in contrast to the aforementioned syndromes resulted in affected female carriers and truncation of the MED12 protein, 28 (ii) a recurrent homozygous MED17 missense variant has been linked to postnatal progressive microcephaly with seizures and brain atrophy (MIM #613668), 29 (iii) a homozygous MED23 variant causes autosomal recessive nonsyndromic ID (MIM #614249), 30 (iv) a homozygous MED25 variant causes autosomal recessive adult onset axonal Charcot-Marie-Tooth neuropathy (CMT2B2, MIM #605589) 31 and (v) a truncation of CDK19 caused by a chromosome inversion is associated with bilateral congenital retinal folds, microcephaly, and mild ID (MIM #614720). 32 We observe that the MED13L phenotype displays similarities to OpitzKaveggia syndrome, along with key differences (see Table 3).…”

MED12 related disorders

“…Recently, parallel sequencing of all X-chromosome exons identified a novel c.5898insC frameshift mutation (p.S1967Qfsx84) of MED12 in a five-generation family with non-syndromic profound X-linked intellectual disability in 10 males and one female [Lesca et al, 2013]. Clinical features common to most affected males were long narrow face, high forehead, flat malar area, high nasal bridge, short philtrum, and absent or severely-limited language (Table I).…”

“…Finally, a large family with profound X-linked intellectual disability was recently found to carry a novel c.5898insC frameshift mutation in MED12 through parallel sequencing of all X-chromosome exons [Lesca et al, 2013]. Dysmorphic features in affected males included narrow face, high forehead, flat malar area, high nasal bridge and short philtrum.…”

Two male sibs with severe micrognathia and a missense variant in MED12

“…However, Risheg et al (2007) noted both random and skewed X-chromosome inactivation patterns in female carriers in Opitz-Kaveggia syndrome. No correlation was found between cognitive function and X-chromosome inactivation pattern in heterozygous females in the single family reported with a MED12 frameshift mutation (Lesca et al, 2013). Whether or not skewed X-chromosome inactivation is a consistent finding associated with certain MED12 genotypes remains to be determined.…”

“…A frameshift mutation in MED12, c.5898dupC in exon 41, which results in generation of an abnormal isoform, was described in a single large family with XLID (Lesca et al, 2013). All hemizygous males were severely intellectually impaired and dysmorphic.…”