HACD1 was first reported in relation to autosomal recessive congenital myopathy in 2013 (Muhammad et al., PMID: 23933735). This first report characterized a proband harboring a nonsense variant, with several other cases detailing a missense variant in a consanguineous family (PMID: 28781516), and a homozygous LINE insertion in Exon 6 (PMID: 32426512). Most recently, three consanguineous probands from different families were characterized each harboring a splice-altering or premature termination variant likely leading to nonsense-mediated decay (PMID: 33354762). Evidence supporting this gene-disease relationship includes six families with case-level data and a large amount of experimental data, including a naturally occuring model of myopathy in canines. Variants in this gene have been reported in six consanguineous probands and segregated with disease in nine additional family members. All variants are absent from gnomAD. The mechanism for disease is homozygous loss of function, with modified very-long-chain fatty acids causing a reduction in membrane flexibility and altering myoblast fusion in development and into adulthood specifically affecting T-tubule organization. This is similar to the pathogenic mechanisms in centronuclear myopathies caused by mutations in BIN1, DNM2, and RYR1 (PMIDs: 26160855, 27939133). While fiber-type disproportion is commonly observed in human probands, centrally nucleated muscle fibers characteristic of the centronuclear myopathies have not. This may be due to the young ages affecting the histological phenotypes or a potential compensatory effect of two HACD1 paralogues - HACD2 and HACD3 (PMID: 33354762). This gene-disease association is supported by both a canine model with a large LINE insertion that eliminates protein expression and a KO mouse model, both of which recapitulate the main muscle-related phenotypes displayed in humans. HACD1's function of moderating myoblast fusion via VLCFAs and the altered effects demonstrated on cultured cells, as well as its relatively high prevalence in skeletal muscle, also provide contributing evidence. In summary, HACD1 is definitively associated with autosomal recessive congenital myopathy. Although the rarity of reported cases previously limited the strength of genetic evidence, the strong experimental evidence and recent probands provide more than sufficent evidence to characterize this relationship.
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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