TNNI2 – Sheldon-Hall syndrome

TNNI2 (troponin I type 2) is implicated in Sheldon-Hall syndrome (distal arthrogryposis type 2B, DA2B), an autosomal dominant disorder characterized by non-progressive congenital limb contractures (Gene Symbol; Sheldon-Hall syndrome).

The overall gene-disease validity meets the ClinGen Strong category based on multiple unrelated families, segregation data, and concordant functional studies.

1 Clinical Validity

Genetic analyses in a cohort of 153 DA1 and DA2B cases identified pathogenic TNNI2 variants in approximately one quarter of 56 mutation-positive kindreds (PMID:23401156).

Additional autosomal dominant segregation in a three-generation Chinese DA2B family (3 affected members) and a Japanese case with paternal somatic mosaicism reinforce locus specificity (PMID:36069346; PMID:36631501).

A knock-in mouse model carrying the p.Lys175Asn variant recapitulates DA2B limb contractures and growth deficit via a bone-specific gain-of-function mechanism (PMID:25340332).

2 Genetic Evidence

Inheritance is autosomal dominant.

At least ~15 probands across unrelated families have TNNI2 pathogenic variants, including recurrent c.525G>T (p.Lys175Asn) (PMID:23401156; PMID:36069346).

Segregation in the Chinese family showed co-segregation in 3 affected relatives, with 2 additional beyond the index case.

Variant spectrum includes missense changes clustering in the actin-binding domain; c.525G>T (p.Lys175Asn) is observed in multiple cohorts.

3 Functional Evidence

The Tnni2 p.Lys175Asn knock-in mouse exhibits limb contractures and reduced body size mirroring DA2B clinical features.

TNNI2 is expressed in osteoblasts and chondrocytes; mutant protein binds the Hif3a promoter with increased transactivation, leading to impaired angiogenesis and delayed ossification (PMID:25340332).

These data support a gain-of-function mechanism directly relevant to human pathology.

4 Conflicting Evidence

No studies to date refute the association or implicate alternative genes in DA2B in these families.

5 Integration & Clinical Utility

Genetic and functional data converge on autosomal dominant TNNI2 gain-of-function variants as a clear cause of DA2B/Sheldon-Hall syndrome.

This robust evidence supports clinical genetic testing for TNNI2 in patients with distal arthrogryposis and informs variant interpretation frameworks.

Key Take-home: Pathogenic TNNI2 missense variants cause autosomal dominant Sheldon-Hall syndrome via a gain-of-function effect on bone development.

References

• American Journal of Medical Genetics Part A • 2013 • Spectrum of mutations that cause distal arthrogryposis types 1 and 2B. PMID:23401156
• PLoS Genetics • 2014 • A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice. PMID:25340332
• Molecular Genetics & Genomic Medicine • 2022 • A TNNI2 variant c.525G>T causes distal arthrogryposis in a Chinese family. PMID:36069346
• Journal of Human Genetics • 2023 • Distal arthrogryposis in a girl arising from a novel TNNI2 variant inherited from paternal somatic mosaicism. PMID:36631501

Evidence Based Scoring (AI generated)