Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: TNNI1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance updated to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 10:47 a.m. | Last Modified: 11 Dec 2025, 10:47 a.m.

Panel Version: 5.24

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update. 3 families with biallelic LOF variants and 3 families with monoallelic GOF variants, presenting with a hypo- or hypercontractile phenotype, respectively.

Created: 18 Jun 2025, 3:45 p.m. | Last Modified: 18 Jun 2025, 3:45 p.m.

Panel Version: 5.7

- PMID: 38569017 (2024) - 9 individuals from 3 families with biallelic LOF variants in the TNNI1 gene, manifesting with early-onset myopathy with progressive muscle weakness (proximal more than distal) and rod formation on histology. 2 individuals from different families presented with severe infantile weakness with minimal attainment of motor milestones. 3 individuals from 2 families had mild/moderate contractures.

Also another 2 families with heterozygous GOF variants, resulting in hypercontractile disease with a constellation of symptoms including muscle cramping, myalgias, stiffness, and rod formation. 4/5 patients reported normal muscle strength and there is no mention of contractures. Recognition of symptoms ranged from childhood to adulthood.

Functional studies in zebrafish demonstrate variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype.


- PMID: 34934811 (2021) - Japanese family with 3 affected individuals with proximal arthrogryposis and elevated CK, albeit without muscle weakness. A presumed GOF heterozygous c.523A>T, p.K175* TNNI1 variant was identified (2 genotyped). Muscle biopsy demonstrated a moth-eaten appearance and mild fibre size variation in type 1 fibres, and electron microscopic analysis revealed type 1 fibre Z disk streaming. No functional studies were done.

Created: 18 Jun 2025, 3:39 p.m. | Last Modified: 18 Jun 2025, 3:39 p.m.

Panel Version: 5.3

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Hypocontractile (AR LOF) or Hypercontractile (AD GOF) muscle disease

Publications

• 38569017
• 34934811

Green List (high evidence)

The study describes: "We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G>A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5."
Sources: Literature

Created: 24 Aug 2024, 1:39 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• PMID: 38569017