Novel compound heterozygous mutation in causes a neurodevelopmental disorder by disrupting cortical proliferation.

Background: Mutations in the gene, which encodes a deubiquitinating isopeptidase called STAM-binding protein, are related to global developmental delay, microcephaly, and capillary malformation. Owing to the limited number of reported cases, the functional and phenotypic characteristics of variants require further elucidation.

Materials And Methods: Whole exome sequencing was performed on a patient presenting with a neurodevelopmental disorder. Novel compound heterozygous mutations in [c.843_844del (p.C282Wfs*11) and c.920G > A (p.G307E)] were identified and validated using Sanger sequencing. A 3D human cortical organoid model was used to investigate the function of and the pathogenicity of the novel mutation (c.920G > A, p.G307E).

Results: The patient was presented with global developmental delay, autism spectrum disorder, microcephaly, epilepsy, and dysmorphic facial features but without apparent capillary malformation on the skin and organs. Cortical organoids with knockout (KO) showed significantly lower proliferation of neural stem cells (NSCs), leading to smaller organoids that are characteristic of microcephaly. Furthermore, disruption did not affect apoptosis in early cortical organoids. After re-expressing wild-type STAMBP, STAMBP , and STAMBP (a known pathogenic mutation) within KO organoids, only STAMBP rescued the impaired proliferation of deficient organoids, but not STAMBP and STAMBP .

Conclusion: Our findings demonstrate that the clinical phenotype of mutations is highly variable, and patients with different mutations show differences in the severity of symptoms. The missense mutation identified here is a novel pathogenic mutation that impairs the proliferation of NSCs in human brain development.