Submission Details

Autosomal recessive

01/15/2020

The SPTBN4 gene is located on chromosome 19 at 19q13.2 and encodes the spectrin beta, non-erythrocytic 4 protein, one of the spectrin family of proteins. The spectrin beta, non-erythrocytic 4 protein is a scaffold protein that links actin cytoskeleton to the plasma membrane and is important for appropriate localization of specific membrane proteins, including ion channels in axons of neurons. SPTBN4 was first related in relation to an autosomal recessive neurodevelopmental disorder in 2017 (28540413: Knierim et al. 2017). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least seven unrelated individuals in four publications, with variants showing segregation with disease in at least two additional family members (28940097: Anazi et al. 2017; 28540413: Knierim et al. 2017; 29861105: Wang et al. 2018; 31857255: Hausler et al. 2019). At least seven unique variants have been reported, all of which were predicted null. Loss of function appears to be the mechanism of disease. This gene-disease association is supported by mouse and piglet models that recapitulate the human phenotype, displaying hypotonia, tremors, neuropathy, myopathy, and central hearing loss (31850074: Derks et al. 2019; 11528393: Parkinson et al. 2001). Expression is specific and consistent with the neuronal/neuromuscular pathology observed in patients and animal models, with high expression in neurons and enrichment in nodes of Ranvier and axon initial segment (11086001: Berghs et al. 2000). In summary, there is strong evidence to support the relationship between SPTBN4 and autosomal recessive SPTBN4-related neurodevelopmental disorder with hypotonia, neuropathy, and deafness. Additional reports in humans published three years from the first proposal of the association are needed to reach a definitive classification.

29861105 31857255 28940097 28540413 11086001 31850074 11528393