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

Abstract

BackgroundMutations in the STAMBP 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 STAMBP variants require further elucidation.Materials and methodsWhole exome sequencing was performed on a patient presenting with a neurodevelopmental disorder. Novel compound heterozygous mutations in STAMBP [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 STAMBP and the pathogenicity of the novel mutation (c.920G > A, p.G307E).ResultsThe 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 STAMBP knockout (KO) showed significantly lower proliferation of neural stem cells (NSCs), leading to smaller organoids that are characteristic of microcephaly. Furthermore, STAMBP disruption did not affect apoptosis in early cortical organoids. After re-expressing wild-type STAMBP, STAMBPG307E, and STAMBPT313I (a known pathogenic mutation) within STAMBP KO organoids, only STAMBPWT rescued the impaired proliferation of STAMBP deficient organoids, but not STAMBPG307E and STAMBPT313I.ConclusionOur findings demonstrate that the clinical phenotype of STAMBP mutations is highly variable, and patients with different STAMBP mutations show differences in the severity of symptoms. The STAMBP missense mutation identified here is a novel pathogenic mutation that impairs the proliferation of NSCs in human brain development.

Novel STAMBP mutations in a Chinese girl with rare symptoms of microcephaly-capillary malformation syndrome and Mowat-Wilson syndrome

“…Multiple generalized capillary malformations were observed in 22 of 24 (92 %) patients studied in previous reports, with only two (8.3 %, 2/24) involving organs other than the skin [ 4 , 5 ]. Here, we present a challenging case of a girl affected by both MIC-CAP and MWS who experienced repeated refractory epistaxis over nine months and failed multiple conventional therapies.…”

“…MIC-CAP is a rare neurodevelopmental disorder characterized by congenital microcephaly, early-onset intractable epilepsy, profound intellectual disability and diffuse cutaneous capillary malformations. Altogether 22 pathogenic mutations in the STAM binding protein gene have been reported in 24 patients from 8 ethnic populations [ [4] , [5] , [6] ]. The patient presented here met most of the characteristics of this novel syndrome just described in 2013 ( Table 2 ).…”

“…MWS is a rare autosomal dominant disorder that shares several clinical manifestations with MIC-CAP [ 5 , 8 ]. Our patient showed a dysmorphic appearance, global developmental delay, progressive microcephaly, and epilepsy and was only initially diagnosed with MWS after the discovery of a pathogenic nonsense mutation in ZEB2.…”

“…Microcephaly-capillary malformation syndrome (MIC-CAP) [ 1 ] is caused by biallelic STAMBP variants [ 2 , 3 ]. Only 24 patients with STAMBP mutations have been reported so far [ [4] , [5] , [6] ]. Microcephaly, generalized capillary malformations on the skin, global developmental delay and intractable epilepsy are the typical clinical manifestations.…”