Paediatric or syndromic cardiomyopathy

Gene: NEB

Red List (low evidence)

Comment on list classification: There is only patient reported in a large cohort study (UK 100,000 genomes project) with unspecified cardiomyopathy and homozygous NEB variant. No further phenotypic information was reported in the publication (PMID:39472908).

All other reported cases did not have confirmed cardiomyopathy (despite some cardiac involvement in a few cases) or had Nemaline myopathy and cardiomyopathy with variants in other genes (e.g. ACTA1).

There is no functional evidence to suggest the association of NEB with cardiomyopathy.

Hence, this gene should be rated red.

Created: 28 Aug 2025, 5:48 p.m. | Last Modified: 28 Aug 2025, 5:48 p.m.

Panel Version: 7.37

Comment on phenotypes: OMIM phenotype accessed on 28 August 2025.

Created: 28 Aug 2025, 5:48 p.m. | Last Modified: 28 Aug 2025, 5:48 p.m.

Panel Version: 7.36

Biallelic variants in NEB are reported to cause Nemaline myopathy 2 (MIM #256030), which is a skeletal muscle disorder with a wide range of severity and age-of-onset. The most common clinical presentation is early-onset (in infancy or childhood) muscle weakness predominantly affecting proximal limb muscles. The OMIM record (MIM #256030) does not list any cardiac presentations as part of the phenotype.

Cardiac involvement has only been reported in very few cases with NEB-related nemaline myopathy in the literature. However, there is no evidence available to suggest that these patients presented with cardiomyopathy (PMIDs: 28131200 (2016); 29070751 (2017, Article in Japanese); 29070751 (2020).

Although a 9-year-old male patient with nemaline myopathy with dilated cardiomyopathy reported in PMID:23650303 (2013), the patient harboured a novel heterozygous ACTA1 variant, which is causative of the disease.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one male patient with unspecified cardiomyopathy was identified with a homozygous splice donor variant in NEB gene (c.2415+1G>A). However, no further information on patient phenotypes was provided in the patient.

Nebulin is primarily expressed in skeletal muscles and expressed at very low levels in heart. In addition, no cardiac phenotype was reported in NEB knockout mouse models (PMID: 26321576, 2015), suggesting that the any cardiac failure in patients with NEB-related Nemaline myopathy may be secondary to respiratory failure.
Sources: Literature

Created: 28 Aug 2025, 5:43 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Nemaline myopathy 2, autosomal recessive, OMIM:256030

Publications

• 23650303
• 26321576
• 28131200
• 29070751
• 29070751
• 39472908