MYH3 variants cause disease either in an autosomal dominant or recessive manner: ‘Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1B’ (CPSFS1B) is inherited recessively and other phenotypes are inherited dominantly. Compound heterozygosity for one loss-of-function variant and one hypomorphic variant (c.-9+1G>A) leads to recessively inherited CPSFS1B. Heterozygous carriers of loss-of-function variants have been described to be healthy. In those sporadic patients who are heterozygous for only one missense variant in MYH3, the mode of inheritance often remains uncertain.
Genetic analysis of the MYH3 gene is challenging as the 5’ UTR region (including the hypomorphic MYH3 variant c.-9+1G>A) is typically not covered in routine whole exome sequencing (WES). Research reports published before 2018 may have overlooked the c.-9+1G>A variant, as it was characterized by Cameron-Christie et al. only in 2018. The carrier frequency of the c.-9+1G>A variant is approximately 1/70 - 1/430 in different populations of the gnomAD database.
MYH3 autosomal recessive