Congenital muscular dystrophy and congenital myopathy

Gene: SPTBN4

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: 2 May 2024, 3:45 p.m. | Last Modified: 2 May 2024, 3:45 p.m.

Panel Version: 0.229

Comment on list classification: Overall there is evidence to support inclusion of this gene with a green rating on this panel. Given the phenotype features severe muscular hypotonia and weakness with relevant age of onset, it is plausible that patients may be tested under the congenital myopathy clinical indication.

Created: 6 Feb 2023, 12:24 p.m. | Last Modified: 6 Feb 2023, 12:24 p.m.

Panel Version: 3.98

Several cases reported in literature with biallelic pathogenic SPTBN4 variants causing Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519). Features include congenital muscular hypotonia and weakness, among other features. First publication by Knierim et al (2017 - PMID: 28540413) described the patient as having congenital myopathy, with type 1 fiber atrophy shown by muscle biopsy. Wang et al (2018 - PMID: 29861105) suggested that muscle involvement is secondary to denervation as opposed to a myopathy - however, in a later study by Buelow et al (2021 - PMID: 33772159) muscle biopsy specimens from affected infants did reveal signs of a primary myopathy as well as of secondary neuropathic features. Furthermore in pigs, deletions in SPTBN4 cause severe myopathy (PMID: 31850074).

Created: 6 Feb 2023, 12:18 p.m. | Last Modified: 6 Feb 2023, 12:18 p.m.

Panel Version: 3.97

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, OMIM:617519

Green List (high evidence)

PMID: 33772159: Four families with five patients harbouring novel homozygous and compound heterozygous SPTBN4. All patients presented with the key features of NEDHND. Additional symptoms comprised horizontal nystagmus, epileptiform discharges in EEG without manifest seizures, and choreoathetosis. Muscle histology revealed both characteristics of myopathy and of neuropathy. The evidence for a myopathy is mostly from the clinical and histopathological findings, but not from functional studies about the role of SPTBN4 in muscle cells. Further studies are thus needed to determine the impact of pathogenic SPTBN4 variants on the muscle cells. The clinical phenotyping and neurophysiological studies suggest that the muscle weakness seen in patients with SPTBN4 disorder may be caused by a combination of axonal neuropathy and congenital myopathy.

Created: 7 Aug 2021, 7:34 a.m. | Last Modified: 7 Aug 2021, 7:34 a.m.

Panel Version: 2.56

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, MIM# 617519

Publications

• 33772159
• 29861105

Comment on list classification: Added to panel based on new gene/phenotype relationship in OMIM but kept rating as red as only 1 reported case to date (PMID:28540413) plus animal model. No disease recorded yet in DD-G2P for SPTBN4.

Created: 15 Aug 2017, 2:01 p.m.

In a boy, born of consanguineous Kurdish parents, with congenital myopathy, neuropathy, and deafness (CMND; MIM:617519), Knierim et al. (2017, PMID:28540413) identified a homozygous truncating mutation in the SPTBN4 gene (Q533X).

Created: 15 Aug 2017, 1:59 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Myopathy, congenital, with neuropathy and deafness, 617519

Publications

• 28540413