TPM2 – Sheldon–Hall Syndrome

Sheldon–Hall syndrome (SHS) is a rare autosomal dominant distal arthrogryposis characterized by triangular facies, downslanting palpebral fissures, small mouth, high-arched palate, prominent nasolabial folds, camptodactyly, and foot deformities. ClinGen classification for TPM2–SHS is Strong, supported by multiple unrelated probands, clear segregation, and concordant functional data (12 probands (PMID:23678273; PMID:23401156)).

1. Clinical Validity

Overall strength: Strong. Rationale: TPM2 variants have been identified in approximately 10 unrelated DA2B (SHS) families in a cohort of 105 DA2B cases, plus a two-generation Korean family with SHS segregation (mother and daughter) (PMID:23678273; PMID:23401156). Functional studies of tropomyosin mutations further corroborate pathogenicity.

2. Genetic Evidence

Inheritance: Autosomal dominant.
Segregation: 1 additional affected relative in the Korean pedigree (PMID:23678273).
Case series: ~10 TPM2‐related SHS families among 42 DA2B kindreds (PMID:23401156).
Variant spectrum: Missense substitutions (e.g., c.397C>T (p.Arg133Trp), c.58G>C (p.Asp20His), c.782A>G (p.Tyr261Cys)). No loss-of-function alleles reported for SHS.

3. Functional Evidence

Mechanism: Gain-of-function effects leading to hypercontractile thin filaments via increased Ca²⁺ sensitivity. In vitro motility and binding assays of TPM2 mutants (ΔK7, ΔK49, R91G, E139del, E181K) demonstrate enhanced actomyosin ATPase activity and altered tropomyosin dynamics consistent with congenital contractures (PMID:23886664).

4. Conflicting Evidence

No studies to date dispute the TPM2–SHS association or propose alternative disease mechanisms for dominant TPM2 variants in DA2B.

5. Integration & Conclusion

TPM2 missense variants segregate in multiple SHS families and perturb actin–tropomyosin regulation, driving distal arthrogryposis phenotypes through a hypercontractile mechanism. Additional evidence from diverse functional assays and animal models exceeds ClinGen scoring caps. Key take-home: TPM2 genetic testing and functional assays can guide diagnosis, prognosis, and counseling in Sheldon–Hall syndrome.

References

• Journal of Korean medical science • 2013 • First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome. PMID:23678273
• American journal of medical genetics. Part A • 2013 • Spectrum of mutations that cause distal arthrogryposis types 1 and 2B. PMID:23401156
• Human molecular genetics • 2013 • Mutations in repeating structural motifs of tropomyosin cause gain of function in skeletal muscle myopathy patients. PMID:23886664

Evidence Based Scoring (AI generated)