TNNI1

Inheritance Pattern: AD

Disease ID:MONDO:0008779

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015738

Submitter: ClinGen

*TNNI1* was first reported in relation to autosomal recessive congenital myopathy in 2024 (Donkervoort *et al.* PMID: 38569017). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in inheritance pattern, molecular mechanism, and phenotypic variability for *TNNI1* variant carriers. Therefore, the following disease entities have been split and curated separately: 1) autosomal recessive congenital myopathy expressed as a hypocontractile phenotype with early-onset; and 2) autosomal dominant congenital myopathy expressed as a hypercontractile phenotype with childhood and adult onset. Evidence supporting this gene-disease relationship include case-level, experimental, and expression data. The initial cohort study by Donkervoort *et al.* identified one splice-site and two missense variants in three probands with childhood onset myopathy with clinical presentations of mainly proximal muscle weakness with varying severity and progression, ptosis, scoliosis, contractures of elbows and hips, severe generalized hypotonia, and presence of nemaline bodies in patient muscle tissue (PMID: 38569017). These probands came from three families, however, disease segregation within each family was limited to one generation. The mechanism of pathogenicity is reported to be loss of function. The gene-disease association is supported by expression data (Uhlen *et al.* PMID: 25613900, Li *et al.* PMID: 36520026) and functional alteration in patient myofiber biopsy (Donkervoort *et al.* PMID: 38569017) which supports a hypocontractile phenotype consistent with a potential loss-of-function mechanism. In summary, there is LIMITED evidence to support the association between *TNNI1* and autosomal recessive congenital myopathy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Congenital Myopathy Gene Curation Expert Panel on the meeting date November 24, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0018958

Submitter: ClinGen

*TNNI1* was first reported in relation to autosomal dominant congenital myopathy in 2024 (Donkervoort *et al.* PMID: 38569017). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in inheritance pattern and phenotypic variability for *TNNI1* variant carriers. Therefore, the following disease entities have been split and curated separately: 1) autosomal recessive congenital myopathy expressed as a hypocontractile phenotype with early-onset; and 2) autosomal dominant congenital myopathy expressed as a hypercontractile phenotype with childhood and adult onset. Evidence supporting this gene-disease relationship include case-level, experimental, and expression data. The initial cohort study by Donkervoort *et al.* identified one missense variant and one in-frame deletion variant in two probands with nemaline myopathy with clinical presentations of mainly muscle cramping, myalgias, stiffness, reduced exercise endurance, fatigue, difficulty swallowing, and presence of nemaline bodies in patient muscle tissue (PMID: 38569017). The mechanism of pathogenicity is reported to be gain of function. In addition, Nishimori *et al.* reported a *TNNI1* nonsense variant in a family with proximal arthrogryposis, joint contractures, serum high creatinine kinase levels, abnormal muscle pathology, and without muscle weakness (PMID: 34934811). Disease segregation within the families reported by Donkervoort “et al.” and Nishimori *et al.* was limited to two generations. The gene-disease association is supported by expression data (Uhlen *et al.* PMID: 25613900, Li *et al.* PMID: 36520026) and functional alteration in patient myofiber biopsy (Donkervoort *et al.* PMID: 38569017) which supports a hypercontractile phenotype consistent with a potential gain-of-function mechanism, however, direct functional evidence and investigation is still required. In summary, there is LIMITED evidence to support the association between *TNNI1* and autosomal dominant congenital myopathy. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. This classification was approved by the ClinGen Congenital Myopathy Gene Curation Expert Panel on the meeting date November 24, 2025 (SOP Version 11).