Genetic epilepsy syndromesGene: SPTBN4
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) 
- Wang et al (2018 - PMID: 29861105) 
- Pehlivan et al (2019 - PMID: 31230720) 
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.
Created: 7 May 2020, 6:25 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519
gene: SPTBN4 was added gene: SPTBN4 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255 Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness MIM#617519 Penetrance for gene: SPTBN4 were set to Complete Review for gene: SPTBN4 was set to GREEN