Congenital myopathy

Gene: TNNI1

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Dec 2025, 5:32 p.m. | Last Modified: 11 Dec 2025, 5:32 p.m.

Panel Version: 6.43

Green List (high evidence)

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.

However, the biallelic phenotype is early onset and more severe, thus is the only MOI relevant to this panel as severe congenital cases are more likely to be tested under this clinical indication.

Created: 18 Jun 2025, 3:45 p.m. | Last Modified: 18 Jun 2025, 3:49 p.m.

Panel Version: 6.2

- 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
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hypocontractile (AR LOF) 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