Two Novel ACTC1 Variants Cause Arthrogryposis Multiplex Congenita
Lauren Kerr1,2, Pierre Moffatt1,3, Lauren Hyer4
1Shriners Hospital for Children, Montreal, Canada.
Clinical Genetics
|July 16, 2026
Summary
Novel ACTC1 gene variants are linked to arthrogryposis multiplex congenita (AMC), a congenital disorder affecting joint mobility. This study identifies new genetic causes and expands the known symptoms associated with ACTC1-related AMC.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Arthrogryposis multiplex congenita (AMC) involves congenital joint contractures.
- ACTC1 gene variants are known to cause heart disorders and have been implicated in AMC.
- The phenotypic spectrum of ACTC1-related AMC requires further characterization.
Purpose of the Study:
- To identify and characterize novel ACTC1 variants associated with AMC.
- To investigate the functional impact of identified ACTC1 variants.
- To expand the understanding of clinical phenotypes in ACTC1-related AMC.
Main Methods:
- Genetic sequencing to identify ACTC1 variants in individuals with AMC.
- Clinical evaluation of affected individuals, including detailed phenotyping.
- In vitro functional assays to assess the impact of variants on protein function (actin filament assembly, protein levels).
Main Results:
- Two novel heterozygous ACTC1 missense variants (p.Glu109Lys and p.Lys217Thr) were identified in individuals with AMC.
- Individual 1 presented with scoliosis; Individual 2 exhibited Shone's complex with coarctation of the aorta, a previously unreported phenotype for ACTC1-related AMC.
- In vitro studies showed p.Glu109Lys impaired actin filament assembly and reduced ACTC1 protein levels, while p.Lys217Thr did not show these effects.
Conclusions:
- The identified ACTC1 variants are novel causes of AMC.
- The study expands the phenotypic spectrum of ACTC1-related AMC, including complex cardiac anomalies.
- Functional data provides insights into the molecular mechanisms underlying ACTC1-related AMC.
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