Congenital myopathy

Gene: TUBA4A

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of monoallelic TUBA4A variants with congenital myopathy. However, there are only three unrelated families reported with biallelic variants and myopathy and none of the cases had congenital or early-onset myopathy. Hence, the gene should be promoted to green rating on this panel in the next GMS update and the MOI should be set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted'.

Created: 9 Jun 2026, 9:51 p.m. | Last Modified: 9 Jun 2026, 9:51 p.m.

Panel Version: 7.55

PMID:38413182 (2024) reported the identification of a recurrent novel heterozygous de novo variant (c.679C>T/ p.Leu227Phe) in the TUBA4A gene in two unrelated Chinese patients with sporadic congenital myopathy (14-year-old and 6-year-old females). The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F variant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model.

PMID:41678358 (2026) reported a multi-centre study in which the authors identified one previously reported and 12 novel TUBA4A missense variants in 31 individuals from 19 unrelated families. Individuals in 17 families presented with a myopathy without any CNS involvement or history of such disease, while probands from the remaining two families presented with cerebellar ataxia and epilepsy accompanying proximal and axial muscle weakness along with protein aggregation.

Four families demonstrated autosomal dominant transmission through heterozygous variants in TUBA4A, three probands had recessive inheritance due to homozygous variants, while the respective heterozygous carriers were asymptomatic; five probands carried de novo variants, and nine probands with heterozygous variants were classified as sporadic cases. Clinical phenotypes ranged from mild to severe myopathy, predominantly affecting the axial and paraspinal muscles. The disease onset ranged from congenital to late adulthood.

Of the three families with homozygous variants, the disease onset/ first clinical examination was only after 10 years in two (although motor delay reported in one family) and the third was 70-year-old patient also with a VUS variant in FLNC gene.

This gene has been associated only with AD congenital myopathy in OMIM (MIM #621225) and the record was last accessed 09 June 2026.

Created: 9 Jun 2026, 9:46 p.m. | Last Modified: 9 Jun 2026, 9:46 p.m.

Panel Version: 7.52

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital myopathy 26, OMIM:621225; congenital myopathy 26, MONDO:0979229

Publications

• 38413182
• 41678358

Green List (high evidence)

novel heterozygous de novo c.679C>T (p.L227F) variant in theTUBA4A(NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles.

Created: 27 May 2026, 9:42 a.m. | Last Modified: 27 May 2026, 9:42 a.m.

Panel Version: 7.25

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 38413182