Nonsyndromic X‐linked intellectual deficiency in three brothers with a novel MED12 missense mutation [c.5922G>T (p.Glu1974His)]

Abstract

Key Clinical MessageX-linked intellectual deficiency (XLID) is a large group of genetic disorders. MED12 gene causes syndromic and nonsyndromic forms of XLID. Only seven pathological mutations have been identified in this gene. Here, we report a novel mutation segregating with XLID phenotype. This mutation could be in favor of genotype–phenotype correlations.

A missense mutation in the catalytic domain of O‐GlcNAc transferase links perturbations in protein O‐GlcNAcylation to X‐linked intellectual disability

“…Furthermore, mutations in OGT trigger alterations in stem cell differentiation and development, affecting neuronal lineages . To date, five OGT mutations, all located to the N‐terminal TPR domain, have been reported in patients with XLID . These patients display developmental delay, facial dysmorphia, clinodactyly and microcephaly.…”

Marked yield of re‐evaluating phenotype and exome/target sequencing data in 33 individuals with intellectual disabilities

“…This patient exhibited no hallmark of these syndromes and presented with a unique phenotype characterized by severe ID and speech delay, hypotonia and ASD. The literature review suggested a fourth MED12‐related disorder, characterized by severe ID and absent or deficient language skills (Bouazzi, Lesca, Trujillo, Alwasiyah, & Munnich, ; Lesca et al, ; Prontera et al, ). Therefore, patient 16, together with the previously reported carriers of the MED12 mutation, showed distinct features that may provide evidence for a fourth MED12‐related disorder.…”

A novel MED12 mutation: Evidence for a fourth phenotype

“…More recently different phenotypes, not completely ascribable to the known three MED12 ‐related disorders, have been reported [Lesca et al, ; Bouazzi et al, ; Langley et al, ; Tzschach et al, ]. In two of these families [Lesca et al, ; Bouazzi et al, ], the MED12 mutations have led to mild ID in females, thus posing concerns about clinical manifestation in heterozygotes, relevant for genetic counseling and prognostic evaluation. Lesca et al [] described a five‐generation family with an apparently non‐syndromic XLID where males and females carried a novel MED12 mutation c.5898dupC.…”

“…Mutations of the MED12 gene at Xq13, encoding a subunit of the mediator complex that plays a central role in RNA polymerase II transcription, have been identified in patients with X‐linked intellectual disability (XLID). To date, at least 10 different MED12 missense mutations are known to be involved in at least three distinctive XLID phenotypes: Opitz–Kaveggia or FG syndrome (FGS1) [OMIM 305450], Lujan–Fryns syndrome [OMIM 309520] and the X‐linked Ohdo syndrome (Maat–Kievit–Brunner type or OSMKB) [OMIM 300895] [Schwartz et al, ; Callier et al, ; Graham and Schwartz, ; Lesca et al, ; Vulto‐van Silfhout et al, ; Isidor et al, ; Bouazzi et al, ; Tzschach et al, ]. Opitz–Kaveggia syndrome is characterized by moderate–severe developmental delay (DD)/intellectual disability (ID), hyperactivity, affability and talkativeness, relative macrocephaly, hypotonia, partial agenesis of the corpus callosum, constipation, broad and flat thumbs, imperforate anus, and minor facial anomalies [Opitz and Kaveggia, ; Risheg et al, ].…”

“…Differently from the other known aforementioned MED12 ‐related disorders, in this family ID was present also in heterozygous females and was particularly severe in affected males. More recently Bouazzi et al [] reported on a novel MED12 missense variant (p.Glu1974His) in three brothers with severe ID and in their mother with a milder phenotype, thus suggesting that not only truncating but also missense mutation can give rise to a severe phenotype in males and milder clinical manifestation in females.…”