EFTUD2 variants were first reported in relation to autosomal dominant mandibulofacial dysostosis-microcephaly syndrome (MFDM) in 2012 (PMID: 22305528). EFTUD2 encodes a GTPase subunit of the U5 small nuclear ribonucleoprotein complex of the spliceosome. MFDM is characterized by global developmental delay, intellectual disability, microcephaly, craniofacial skeletal anomalies, and abnormalities of the ears and hearing (PMIDs: 22305528, 24999515, 35395430). To date, at least 126 MFDM patients have been reported with EFTUD2 variants, including large deletions, nonsense, frameshift, splice site, and missense variants (PMIDs: 22305528, 24999515, 35395430). Nine unique variants reported in nine probands (PMIDs: 22305528, 35395430) are included in this curation. Most cases are de novo, although inheritance from mildly affected parents has been reported in rare cases (PMID: 24999515). The mechanism of pathogenicity is haploinsufficiency. Homozygous EFTUD2 knock-out zebrafish and mice with a homozygous conditional EFTUD2 knock-out in neural crest cells display abnormal brain development, abnormal craniofacial malformations, and abnormal splicing, which further supports the gene-disease relationship (PMIDs: 27899647, 33601405).
In summary, there is definitive evidence supporting the relationship between EFTUD2 and autosomal dominant mandibulofacial dysostosis-microcephaly syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 20, 2022 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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