Submission Details

The MYMK gene, previously referred to as TMEM8C, is located on chromosome 9 at 9q34.2 and encodes the transmembrane Myomaker protein, which is required for myoblast fusion and the formation of multinucleated myofibers during skeletal muscle development and regeneration. The MYMK gene was first reported in relation to autosomal recessive Carey-Fineman-Ziter syndrome in 2017 (Di Gioia et al., PMID: 28681861). One initiation codon, one non-canonical splice site, and six unique missense alleles have been reported in humans. A majority of individuals carry one copy of the p.Pro91Thr variant. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in nine unrelated probands in five publications (PMID: 28681861; Alrohaif et al., 2018, PMID:29560417; Hedberg-Oldfors et al., 2018, PMID:30065953; Camacho et al., 2020, PMID:32333597; Lunke et al., 2020, PMID:32573669). Variants in this gene segregated with disease in five additional family members, but none of the families met criteria for scoring segregation. Homozygous loss of function is implicated as the mechanism of disease. This gene-disease relationship is also supported by expression data, in vitro functional analyses of reported variants, mouse and zebrafish models, and rescue in the zebrafish model (Millay et al., 2013, PMID:23868259; PMID: 28681861). In summary, MYMK is definitively associated with autosomal recessive Carey-Fineman-Ziter syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 03.02.2022 (SOP Version 8).