TNNT3 – Nemaline Myopathy

TNNT3 encodes the fast skeletal muscle troponin T subunit and has historically been implicated in autosomal dominant distal arthrogryposis. Nemaline myopathy is a rare congenital myopathy characterized by hypotonia, contractures and nemaline rod accumulation in fast fibers. Although TNNT3 had not been associated with nemaline myopathy, two independent reports now describe biallelic TNNT3 splice-site variants in patients with severe neonatal myopathy.

In the initial case, a male neonate presented with severe weakness, hypotonia (HP:0001252), flexion contractures (HP:0001371) and congenital scoliosis. Muscle biopsy showed fast-fiber atrophy with striking nemaline rods and slow-fiber hypertrophy. Targeted gene panel sequencing identified a homozygous essential splice donor variant in TNNT3 (c.681+1G>A) that disrupted normal splicing, eliciting exon skipping and intron retention (PMID:29266598).

A second individual described in Neurology: Genetics harbored a homozygous splice acceptor variant c.481-1G>A, presenting with limb, bulbar and respiratory weakness that improved over time, hypotonia, scoliosis (HP:0002650) and high-arched palate (HP:0000218) (PMID:33977145). Unlike the first patient, nemaline rods and distal arthrogryposis were absent, illustrating phenotypic variability among recessive TNNT3-related congenital myopathies.

Both splice variants segregate with disease in an autosomal recessive manner. To date, only these two unrelated probands have been reported, and no additional affected relatives have been documented. The variant spectrum in TNNT3-related nemaline myopathy comprises essential splice junction mutations leading to loss of function.

Functional studies of c.681+1G>A confirmed aberrant TNNT3 transcripts with frameshift consequences and Western blot demonstrated near-total absence of troponin-Tfast with secondary loss of troponin-Ifast (PMID:29266598). This loss-of-function mechanism is consistent with impaired thin filament regulation and nemaline rod formation in fast fibers.

Collectively, two unrelated probands with biallelic TNNT3 splice variants and concordant functional data support a Moderate level of gene–disease validity. TNNT3 should be incorporated into genetic testing panels for congenital nemaline myopathy, particularly in presentations with early hypotonia, contractures and nemaline rods.

References

• Human Mutation • 2018 • Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant PMID:29266598
• Neurology: Genetics • 2021 • Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy PMID:33977145

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