Intellectual disability
Gene: SPTBN4

SPTBN4 (spectrin beta, non-erythrocytic 4)
EnsemblGeneIds (GRCh38): ENSG00000160460
EnsemblGeneIds (GRCh37): ENSG00000160460
OMIM: 606214, Gene2Phenotype
SPTBN4 is in 7 panels

3 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.

Panel Version: 3.1510

Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

Arina Puzriakova (Genomics England Curator)

Review by Helen Brittain (Genomics England Clinical Team): the phenotype is characterised by marked hypotonia in infancy and developmental delay / ID. Adding as Green to the ID panel would therefore cover both of these GMS indications (as the Hypotonic Infant super panel has the ID panel as a sub-panel).
Created: 10 Nov 2020, 4:42 p.m. | Last Modified: 10 Nov 2020, 4:42 p.m.

Panel Version: 3.510

Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update.

Severe-to-profound DD and/or ID reported in all but one family with a milder phenotype (at least 9 total families described with different biallelic variants in SPTBN4).
Created: 5 Oct 2020, 2:03 p.m. | Last Modified: 5 Oct 2020, 2:03 p.m.

Panel Version: 3.378

Created: 5 Oct 2020, 2:03 p.m.
Last Modified: 5 Oct 2020, 2:03 p.m.
Panel version: 3.510

Konstantinos Varvagiannis (Other)

Green List (high evidence)

** Consider also the GeneReview on this disorder - PMID : 32672909
Created: 17 Sep 2020, 9:29 p.m. | Last Modified: 17 Sep 2020, 9:29 p.m.

Panel Version: 3.314

Biallelic pathogenic SPTBN4 variants cause Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (MIM #617519).

There are several reports on the phenotype of relevant affected individuals with severe/profound DD/ID in at least 9 individuals :

- Knierim et al (2017 - PMID: 28540413) [1 affected individual]
- Anazi et al (2017 - PMID: 28940097) [1]
- Wang et al (2018 - PMID: 29861105) [6]
- Pehlivan et al (2019 - PMID: 31230720) [1]

A recent article by Häusler et al (2019 - PMID: 31857255) describes the phenotype of 2 sibs, both presenting with motor and speech delay, although the older one had reportedly 'normal' cognitive performance allowing attendance of regular school at the age of 6 years.

Features include congenital hypotonia, severe DD and ID (in most as outlined above, ID was the primary indication for testing on several occasions), poor or absent reflexes and weakness secondary to axonal motor neuropathy, feeding and respiratory difficulties, hearing and visual impairment. Seizures have been reported in at least 4 unrelated individuals (3 by Wang et al / 1 by Pehlivan et al).

Variants in most cases were nonsense/frameshift although biallelic missense variants have also been reported. Sibs in the report by Häusler et al harbored a homozygous splicing variant.

SPTBN4 encodes a member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle.

βIV spectrin links ankyrinG and clustered ion channels (at axon initial segments and nodes of Ranvier) to the axonal cytoskeleton. Pathogenic variants are proposed to disrupt the cytoskeletal machinery controlling proper localization of ion channels and function of axonal domains where ion channels are normally clustered in high density. Among the evidence provided : nerve biopsies from an affected individual displayed reduced nodal Na+ channels and no nodal KCNQ2 K+ channels / Loss of AnkyrinG and βIV spectrin in animal model resulted in loss of KCNQ2- and KCNQ3- subunit containing K+ channels.

Apart from the ID / epilepsy panels please consider inclusion in other relevant ones.
Sources: Literature
Created: 7 May 2020, 6:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Publications

Created: 7 May 2020, 6:23 a.m.

Panel version: 3.314

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green

Phenotypes

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

OMIM

606214

Clinvar variants

Variants in SPTBN4

Penetrance

Complete

Publications

Panels with this gene