MEGF8 was first reported in relation to autosomal recessive Carpenter syndrome as early as 2012 (Twigg et al., PMID: 23063620). At least six different variants (missense, nonsense, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation includes six variants described in four probands in one publication (PMID: 23063620). In addition, we included one internal case, a proband with Carpenter syndrome who was compound heterozygous for c.4872delG (p.Phe1625Serfs) and c.7769_7771delCCT (p.Ser2590del), to reach a score of 6 points for genetic evidence. The mechanism of disease is proposed to be partial loss of function (PMID: 26340332). This gene-disease relationship is also supported by mouse models, expression data, and in vitro functional assays (PMID: 19218456, 23063620, 24052814, 32203821, 32966817). In summary, there is moderate evidence to support the relationship between MEGF8 and autosomal recessive Carpenter syndrome. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This curation was approved by the Craniofacial Malformations Gene Curation Expert Panel on 6/17/21 (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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