Two Novel ACTC1 Variants Cause Arthrogryposis Multiplex Congenita.

Arthrogryposis multiplex congenita (AMC) is a group of conditions with congenital joint contractures in at least two body regions. ACTC1 variants cause heart disorders but have also been reported in six families with AMC. We report on two individuals with AMC who were heterozygous for ACTC1 missense variants (NM_005159.5; c.325G>A, p.Glu109Lys and c.650A>C, p.Lys217Thr). Individual 1 had scoliosis and no reported cardiac phenotype. Individual 2 had Shone's complex with coarctation of the aorta, which has not been reported in ACTC1-related AMC before. In vitro testing demonstrated that p.Glu109Lys caused impaired actin filament assembly and reduced ACTC1 protein levels, effects not apparent for p.Lys217Thr. Our findings characterize two novel variants that cause ACTC1-related AMC and expand the list of phenotypes observed in this disorder.