MYH3 – Freeman-Sheldon Syndrome

Freeman-Sheldon syndrome (FSS; MONDO:0008675) is a rare autosomal dominant distal arthrogryposis characterized by camptodactyly, ulnar deviation, talipes equinovarus, and distinctive facial features including long philtrum, hypertelorism, blepharophimosis, a small pinched nose, and pursed mouth. FSS has been attributed to pathogenic missense mutations in the embryonic myosin heavy chain gene MYH3 (HGNC:7573).

Multiple independent case reports describe de novo heterozygous MYH3 variants in unrelated probands presenting with classic FSS features. An Egyptian infant was found to carry a de novo c.2014C>T (p.Arg672Cys) mutation (PMID:20924721), while three further unrelated cases harbored the recurrent c.2015G>A (p.Arg672His) variant (PMID:26996280; PMID:28584669; PMID:34664542). No family history of FSS or consanguinity was reported in these cases, consistent with dominant de novo inheritance.

Segregation analysis is limited by the absence of affected relatives; one phenotypically normal mother was confirmed as a somatic mosaic carrier of the p.Arg672His variant, indicating gonadal mosaicism and elevated recurrence risk (PMID:26996280).

The variant spectrum in FSS is dominated by missense substitutions clustering at residues critical for myosin catalytic function. The recurrent Arg672 substitutions impair motor domain activity, and no loss-of-function alleles have been reported in dominant FSS, supporting a dominant-negative mechanism.

Functional studies demonstrate that FSS-associated MYH3 mutations disrupt myosin ATPase activity and myofiber force production. Structure–function analyses predict interference with lever arm priming, while Drosophila models expressing p.Arg672His or p.Thr178Ile show sarcomere defects, reduced ATPase rates, and impaired locomotion, paralleling the human phenotype (PMID:16642020; PMID:30826400).

Together, robust genetic and functional evidence supports a strong clinical validity for MYH3 in FSS. Genetic testing for MYH3 missense variants enables definitive diagnosis, informs recurrence risk, and guides multidisciplinary management including orthopedic and anesthetic planning.

References

• Indian journal of pediatrics • 2011 • p.R672C mutation of MYH3 gene in an Egyptian infant presented with Freeman-Sheldon syndrome. PMID:20924721
• American journal of medical genetics. Part A • 2016 • Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation. PMID:26996280
• Case reports in genetics • 2017 • Freeman-Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa. PMID:28584669
• Ophthalmic genetics • 2022 • A case of blepharophimosis: Freeman Sheldon syndrome. PMID:34664542
• Nature genetics • 2006 • Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. PMID:16642020
• Developmental biology • 2019 • Myosin heavy chain mutations that cause Freeman-Sheldon syndrome lead to muscle structural and functional defects in Drosophila. PMID:30826400

Evidence Based Scoring (AI generated)