MYH8 – Trismus-pseudocamptodactyly Syndrome

Trismus-pseudocamptodactyly syndrome (TPS) is a rare autosomal dominant distal arthrogryposis characterized by congenital inability to open the mouth fully (trismus) and flexion deformities of the fingers upon wrist dorsiflexion (pseudocamptodactyly). The disorder is caused by missense mutations in the perinatal myosin heavy chain gene MYH8, leading to functional impairment of the contractile apparatus in facial and limb muscles.

Initial evidence came from a large family with familial cardiac myxomas and TPS, in which linkage analysis localized the disease to chromosome 17p12–p13.1 (maximum multipoint LOD 4.39) and identified a recurrent missense variant, c.2021G>A (p.Arg674Gln), in MYH8 ([PMID:15282353]). The same variant was subsequently observed in two unrelated TPS pedigrees within this study. Further screening of four independent TPS families confirmed c.2021G>A (p.Arg674Gln) as a founder and recurrent mutation in both European and North American populations ([PMID:17041932]).

Autosomal dominant inheritance is supported by segregation of c.2021G>A across at least seven affected individuals from six unrelated pedigrees with clear parent-to-child transmission and absence of alternative pathogenic variants. No loss-of-function alleles in MYH8 have been associated with TPS, and heterozygous truncating variants are present in population databases without clinical manifestations, underscoring a missense-specific dominant-negative mechanism ([PMID:28377322]).

Biochemical studies of the homologous p.Arg674Gln mutation demonstrate significant reductions in single-molecule step size and actin-detachment rates, as well as slowed ATPase cycle kinetics, correlating with severe distal arthrogryposis phenotypes ([PMID:38377203]). These findings support a dominant-negative effect of the mutant perinatal myosin heavy chain, disrupting myofibrillar contractility in orofacial and distal limb muscles.

No studies have refuted the pathogenicity of c.2021G>A (p.Arg674Gln); the absence of TPS in individuals carrying other MYH8 variants and the strong segregation data mitigate conflicting evidence. Functional concordance between molecular defects and clinical severity further consolidates the causal relationship.

On integration, the recurrent c.2021G>A (p.Arg674Gln) variant in MYH8 meets criteria for a Strong gene-disease association. Genetic testing focusing on this hotspot variant enables rapid diagnosis of TPS, informs reproductive counseling, and guides early intervention strategies for trismus management.

Key Take-home: A recurrent AD missense mutation, c.2021G>A (p.Arg674Gln), in MYH8 causes TPS via a dominant-negative disruption of perinatal myosin motor function, supporting targeted genetic testing for clinical diagnosis.

References

• The New England Journal of Medicine • 2004 • Mutation of perinatal myosin heavy chain associated with a Carney complex variant. PMID:15282353
• American Journal of Medical Genetics. Part A • 2006 • Trismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8. PMID:17041932
• Proceedings of the National Academy of Sciences of the United States of America • 2024 • Homologous mutations in human β, embryonic, and perinatal muscle myosins have divergent effects on molecular power generation. PMID:38377203
• European Journal of Medical Genetics • 2017 • Caution in interpretation of disease causality for heterozygous loss-of-function variants in the MYH8 gene associated with autosomal dominant disorder. PMID:28377322

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