A novel homozygous nonsense mutation of VPS13B associated with previously unreported features of Cohen syndrome

Abstract

Cohen syndrome (CS) is a rare autosomal recessive disorder associated with mutations in the vacuolar protein sorting 13 homolog B (VPS13B; formerly COH1) gene. The core clinical phenotype comprises a characteristic facial gestalt, marked developmental delay, and myopia. Additional, nonobligatory features include obesity, microcephaly, short stature, muscular hypotonia, scoliosis, narrow hands and feet, progressive retinopathy, as well as neutropenia. Here we report a novel homozygous nonsense mutation in the VPS13B gene and previously undescribed clinical features in a 19‐year‐old woman with developmental delay, intellectual disability, and a particular facial appearance. The patient showed several features consistent with CS. In addition, the parents observed congenital alacrima and anhidrosis persisting until onset of puberty. The diagnosis was not established based on the clinical phenotype. We performed whole‐genome sequencing and identified a novel homozygous nonsense mutation c.62T>G (NM_152564.4), p.(Leu21*) in the VPS13B gene. Our findings extended the previously reported phenotype of CS. We conclude that transient, prepubertal alacrima and anhidrosis are part of the phenotypic spectrum of CS associated with a novel homozygous nonsense mutation in the VPS13B gene.

A Novel Homozygous VPS13B Splice-Site Mutation Causing the Skipping of Exon 38 in a Chinese Family With Cohen Syndrome

“…CS has been attributed to loss-of-function biallelic mutations in the VPS13B gene. Since the founder mutation c.3348_3349delCT was found in Finnish patients, more than 200 causative mutations have been reported so far in ∼1,000 CSaffected individuals worldwide including non-sense, duplication, missense, splicing, insertion/deletion mutations (7,15,17). VPS13B maps to chromosome 8q22.2 and encodes six protein isoforms generated by alternative splicing (https://www.uniprot.…”

“…To date, clear phenotype-genotype correlations of CS have not been established yet. Although CS-affected individuals from outside Finland present with variable phenotypes (15), the typical clinical characteristics usually include intellectual disability, short stature, a cheerful disposition, retinal dystrophy, hypotonia, scoliosis, joint laxity, intermittent neutropenia, slender fingers, hyperlinear palms, midchildhood onset truncal obesity and craniofacial dysmorphisms such as microcephaly, thick hair, low hairline, short philtrum, wave-shaped eyes and prominent upper central incisors (1,16,17).…”

“…VPS13B is localized on chromosome 8 (8q22.2) with 62 exons and encodes a 4022-amino acid transmembrane protein (14). The encoded protein is a Golgi-associated peripheral membrane protein that plays an important role in Golgi integrity and homeostasis, and membrane transport (17,19), and it belongs to the VPS13 protein family, which are highly conserved in eukaryotic cells (20,21). Loss-of-function mutations in other VPS13 family members such as VPS13A, VPS13C, and VPS13D could result in choreaacanthocytosis (OMIM 200150), rapidly progressive, earlyonset autosomal recessive Parkinson's disease (OMIM 616840) and spinocerebellar ataxia, recessive type 4 (OMIM 607317), respectively (22)(23)(24).…”

Identification of a Novel VPS13B Mutation in a Chinese Patient with Cohen Syndrome by Whole-Exome Sequencing

“…The clinical manifestations of patients with Cohen syndrome vary widely. Most patients do not show typical clinical manifestations until school age or later, making early diagnosis difficult, 7,[12][13][14] and therefore, early diagnosis relies on genetic testing. Currently, Finns have been reported to exhibit similar phenotypes.…”

Exploring the pathological mechanisms underlying Cohen syndrome

“…Brain structural abnormalities have been reported in some patients using cerebral magnetic resonance imaging (MRI). These include thick corpus callosum ( Kivitie-Kallio et al, 1998 ; Mochida et al, 2004 ; Rejeb et al, 2017 ; Koehler et al, 2020 ), thin corpus callosum ( Alipour et al, 2020 ), atrophy of the cerebellar vermis ( Mochida et al, 2004 ; Waite et al, 2010 ), pontocerebellar atrophy ( Katzaki et al, 2007 ), thinning of the cortex ( Hu et al, 2021 ) and cerebral atrophy ( Ghzawi et al, 2021 ). The disease-causing gene was identified in 2003 and originally named COH1 , later renamed VPS13B , by homology with the yeast protein ( Kolehmainen et al, 2003 ).…”