MED12 – X-linked intellectual disability with marfanoid habitus

MED12 (HGNC:11957) has been implicated in X-linked intellectual disability with marfanoid habitus (MONDO:0010655). Affected males present with variable intellectual disability, marfanoid habitus including disproportionate tall stature (HP:0001519), hypernasal speech (HP:0001611), and characteristic facial features such as a high forehead, prominent nasal bridge, and short philtrum (HP:0000271).

Genetic studies report four unrelated pedigrees encompassing 17 affected individuals with hemizygous MED12 variants, consistent with X-linked recessive inheritance and skewed X-inactivation in carrier females (7 affected relatives)[PMID:24039113]. Variant classes include a frameshift c.5898dupC (p.Ser1967GlnfsTer?) [PMID:24039113], and three hypomorphic missense changes: c.1862G>A (p.Arg621Gln) [PMID:27286923], c.3020A>G (p.Asn1007Ser) [PMID:27980443], and c.3883C>T (p.Arg1295Cys) [PMID:31536828]. These alleles map to conserved domains of MED12 without a clear founder effect.

Functional assays in patient-derived lymphoblasts demonstrate dysregulated Gli3-dependent Sonic Hedgehog (SHH) signaling, with elevated CREB5, BMP4, and NEUROG2 expression in cells carrying LS-domain mutations, supporting a mechanism of MED12 haploinsufficiency and altered transcriptional coactivation [PMID:30729724].

Notably, a screen of 28 males with a clinical diagnosis of Lujan-Fryns syndrome failed to identify MED12 mutations, highlighting the importance of molecular confirmation in syndromic XLID ([PMID:26358559]).

Collectively, strong genetic evidence from multiple kindreds and moderate experimental concordance establish MED12 as a definitive cause of X-linked intellectual disability with marfanoid habitus. Molecular diagnosis enables precise genetic counseling and informs potential therapeutic targeting of SHH pathway dysregulation.

References

• American journal of medical genetics. Part A • 2013 • Clinical and neurocognitive characterization of a family with a novel MED12 gene frameshift mutation. PMID:24039113
• European journal of medical genetics • 2016 • Two male sibs with severe micrognathia and a missense variant in MED12. PMID:27286923
• Clinical medicine insights. Case reports • 2016 • Lujan-Fryns Syndrome (LFS): A Unique Combination of Hypernasality, Marfanoid Body Habitus, and Neuropsychiatric Issues, Presenting as Acute-Onset Dysphagia. PMID:27980443
• European journal of medical genetics • 2020 • MED12 missense mutation in a three-generation family. Clinical characterization of MED12-related disorders and literature review. PMID:31536828
• Molecular genetics & genomic medicine • 2019 • Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders. PMID:30729724
• American journal of medical genetics. Part A • 2016 • Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities? PMID:26358559

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