Loss of function of SVBP leads to autosomal recessive intellectual disability, microcephaly, ataxia, and hypotonia

BSTRACT Purpose Identifying and characterizing novel causes of autosomal recessive intellectual disability based on systematic clinical and genetic evaluation, followed by functional experiments. Methods Clinical examinations, genome-wide positional mapping, and sequencing were followed by quantitative polymerase chain reaction and western blot of the protein SVBP and its interaction partners. We then knocked down the gene in rat primary hippocampal neurons and evaluated the consequences on synapses. Results We identified a founder, homozygous stop-gain variant in SVBP (c.82C>T; p.[Gln28*]) in four affected individuals from two independent families with intellectual disability, microcephaly, ataxia, and muscular hypotonia. SVBP encodes a small chaperone protein that transports and stabilizes two angiogenesis regulators, VASH1 and VASH2. The altered protein is unstable and nonfunctional since transfected HeLa cells with mutant SVBP did not reveal evidence for immunoreactive SVBP protein fragments and cotransfection with VASH1 showed a severe reduction of VASH1 in medium and cell lysate. Knocking down Svbp in rat primary hippocampal neurons led to a significant decrease in the number of excitatory synapses. Conclusion SVBP is not only involved in angiogenesis, but also has vital functions in the central nervous system. Biallelic loss-of-function variants in SVBP lead to intellectual disability.