EFTUD2 – Mandibulofacial Dysostosis with Microcephaly Syndrome

Mandibulofacial Dysostosis with Microcephaly Syndrome (MFDM) is an autosomal dominant craniofacial disorder caused by heterozygous loss-of-function of EFTUD2. Affected individuals present with microcephaly, mandibular and malar hypoplasia, cleft palate, dysplastic ears, sensorineural hearing loss, and global developmental delay (HP:0000252, HP:0000175, HP:0000365, HP:0001263).

Genetic evidence for EFTUD2-MFDM is robust. Initial whole-exome sequencing of four unrelated probands identified de novo EFTUD2 mutations, and validation in eight additional individuals confirmed causality (12 probands total) (PMID:22305528). Subsequent reviews have described 107 affected individuals from 94 unrelated families harboring 76 distinct loss-of-function or splice variants, with de novo origin in 75% and dominant inheritance in 19% of cases (PMID:26507355).

Variants span frameshifts, nonsense, splice-site, start-loss, and microdeletions, consistent with haploinsufficiency. Familial segregation has been observed in at least 12 kindreds with dominantly inherited EFTUD2 variants (affected_relatives: 12). A representative variant is c.259C>T (p.Gln87Ter) identified de novo in a parent–proband trio (PMID:28643921).

Functional studies in vertebrate models confirm the pathogenic mechanism. Zebrafish eftud2 mutants display craniofacial and neural progenitor apoptosis via p53 activation, with rescue upon p53 inhibition (PMID:27899647). Conditional Eftud2 deletion in mouse neural crest cells leads to mis-splicing of Mdm2, elevated nuclear p53, and craniofacial defects ameliorated by p53 pathway inhibition (PMID:33601405).

At the molecular level, EFTUD2 encodes a U5 snRNP spliceosomal GTPase essential for pre-mRNA splicing. Haploinsufficiency disrupts spliceosome activation and disassembly, triggering p53-dependent apoptosis in neural crest derivatives and resulting in the MFDM phenotype.

In sum, MFDM due to EFTUD2 haploinsufficiency is a definitive gene–disease association, underpinned by over 100 probands, strong segregation data, and concordant functional models. EFTUD2 testing should be included in diagnostic panels for patients with microcephaly and mandibulofacial dysostosis. Key take-home: EFTUD2 haploinsufficiency causes a distinct autosomal dominant MFDM syndrome via spliceosomal dysfunction and p53-mediated neural crest apoptosis.

References

• American Journal of Human Genetics • 2012 • Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. PMID:22305528
• Human Mutation • 2016 • Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update. PMID:26507355
• Orthodontics & Craniofacial Research • 2017 • Whole-exome sequencing identified a variant in EFTUD2 gene in establishing a genetic diagnosis. PMID:28643921
• Nucleic Acids Research • 2017 • Spliceosomal protein eftud2 mutation leads to p53-dependent apoptosis in zebrafish neural progenitors. PMID:27899647
• Human Molecular Genetics • 2021 • Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53. PMID:33601405

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