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

Abstract

Background: Cohen syndrome (CS) is a clinically heterogeneous disorder characterized by extensive phenotypic variation with autosomal recessive inheritance. VPS13B was identified to be the disease-causing gene for CS. The objectives of the present study were to screen likely pathogenic mutations of the patient with developmental delay and mental retardation, and to determinate the effect of this splice-site mutation by reverse transcription analysis.Methods: Whole exome sequencing (WES) in combination with Sanger sequencing were performed to identify the causative mutations of this CS family. Subsequently, the impact of the intronic variant on splicing was analyzed by reverse transcription and the construction of expression vector.Results: A novel homozygous splice-site mutation (c.6940+1G>T) in the VPS13B gene was identified in this proband. Sanger sequencing analysis of the cDNA demonstrated that the c.6940+1G>T variant could cause the skipping of entire exon 38, resulting in the loss of 208 nucleotides and further give rise to the generation of a premature in-frame stop codon at code 2,247.Conclusions: The homozygous VPS13B splicing variant c.6940+1G>T was co-segregated with the CS phenotypes in this family and was identified to be the cause of CS after comprehensive consideration of the clinical manifestations, genetic analysis and cDNA sequencing result.

A Novel Variant in VPS13B Underlying Cohen Syndrome

“…In this study, we report a novel genetic variant in VPS13B [NM_017890.5, c.8841G > A: p.(W2947 ∗ )] in an autosomal recessive consanguineous Pakistani CS family. Over 200 variants have been reported worldwide in multiple domains of VPS13B associated with CS [ 34 ]. VPS13B protein has ten transmembrane domains and a potential vacuolar targeting motif, an endoplasmic reticulum retention signal on the C-terminus and two peroxisomal matrix protein targeting signal 2 (PTS2) consensus sequence both on the N- and C-terminus ( Figure 2(a) ) [ 35 ].…”

Characterization of a loss-of-function NSF attachment protein beta mutation in monozygotic triplets affected with epilepsy and autism using cortical neurons from proband-derived and CRISPR-corrected induced pluripotent stem cell lines

“…The missense variant found in the probands is potentially deleterious given that it is homozygous with a CADD score of 33. Loss-of-function (LoF) mutations in VPS13B have been previously linked to Cohen syndrome ( Kolehmainen et al, 2003 ; Mochida et al, 2004 ; Momtazmanesh et al, 2020 ; Li et al, 2021 ), a rare disorder associated with developmental delay, facial dysmorphisms, and learning disabilities, a spectrum of features seen in the triplet probands ( Kivitie-Kallio and Norio, 2001 ). However, the early onset of epilepsy observed in the probands was not a reported feature of Cohen syndrome, and other features of Cohen syndrome were absent, suggesting that additional genetic variants in the triplets are contributing to the unique clinical phenotype.…”

Cohen Syndrome: Novel VPS13B Genetic Variants in a Male Portuguese Patient with Pigmentary Retinopathy

“…Posteriorly, an extended panel of 16 Finnish families with Cohen syndrome underwent linkage disequilibrium and haplotype analysis, allowing for a refined mapping of the VPS13B gene [3]. Since then, more than 200 cases have been reported worldwide [4], and whole-exome sequencing has enabled the documentation of multiple VPS13B pathogenic variants [5][6][7][8][9][10]. The VPS13B/COH1 gene encodes the VPS13B protein, which is part of the cell's Golgi apparatus and is involved in protein glycosylation and sorting and transporting proteins inside the cell.…”