MYH3 – Contractures, pterygia, and variable skeletal fusions syndrome 1B

The embryonic myosin heavy chain gene MYH3 has been implicated in a spectrum of distal arthrogryposis syndromes and, more recently, in autosomal recessive Contractures, pterygia, and variable skeletal fusions syndrome 1B (MONDO:0020746). CPSKF1B is ultrarare, characterized by multi-articular contractures, skin webbing (pterygia), and spondylocarpotarsal fusion, with fewer than two dozen individuals reported to date. Accurate molecular diagnosis is critical for genetic counselling given overlapping phenotypes with other multiple pterygium syndromes.

In an initial report of four unrelated probands, each carried compound heterozygous or homozygous MYH3 variants that co-segregated with disease under an autosomal recessive model ([PMID:32902138]). Variants included a predicted loss-of-function nonsense allele c.1053C>G (p.Tyr351Ter) in trans with splice region change c.3102+5G>C, and a hypomorphic splice donor variant c.-9+1G>A. More recently, a single male proband was found to harbor compound heterozygous variants c.3377A>G (p.Glu1126Gly) and c.5161-2A>C through whole-exome sequencing and family segregation analysis ([PMID:38444278]).

Segregation studies demonstrated that unaffected parents and siblings were heterozygous carriers, while all affected individuals were trans-compound heterozygotes or homozygotes. No additional affected relatives beyond the probands were reported. Overall, five probands have been documented across five families ([PMID:32902138], [PMID:38444278]). All variants are either absent or extremely rare in population databases.

Functional assays support a loss-of-function mechanism. The missense variant c.3377A>G (p.Glu1126Gly) disrupts local hydrogen bonding within the myosin head and perturbs TGF-β signalling. The splice-site variant c.5161-2A>C induces multiple aberrant transcripts on mRNA analysis, and the hypomorphic c.-9+1G>A allele yields reduced embryonic MyHC levels in patient-derived cells.

No conflicting evidence has been described to date. The concordant segregation across multiple families, combined with in vitro structural and splicing data, supports a Moderate level of clinical validity by ClinGen criteria.

Collectively, biallelic MYH3 variants are established as a cause of autosomal recessive CPSKF1B. Molecular testing of MYH3 should be included in diagnostic panels for multiple pterygium syndromes. Key take-home: MYH3 recessive variants cause CPSKF1B with consistent contractures, pterygia, and vertebral fusions, enabling precise diagnosis and counselling.

References

• American journal of medical genetics. Part A • 2020 • Recessive MYH3 variants cause "Contractures, pterygia, and variable skeletal fusions syndrome 1B" mimicking Escobar variant multiple pterygium syndrome PMID:32902138
• Molecular genetics & genomic medicine • 2024 • Functional assessment of a novel biallelic MYH3 variation causing CPSKF1B (contractures, pterygia, and spondylocarpotarsal fusion syndrome1B) PMID:38444278

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