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

Liangshan Li,Shiguo Liu,Yuhua Ji,Xiangmao Bu,Ping Tan

doi:10.3389/fped.2021.651621

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.

Highlights

Cohen syndrome (CS) (OMIM 216550), initially described in three patients by Cohen et al, is an uncommon autosomal recessive neurodevelopmental disorder with more than 200 causative mutations in ∼1,000 CS-affected individuals reported to date worldwide [1,2,3]
We investigated a pedgree with CS from Shandong province, China and identified a novel homozygous splicing mutation in the Vacuolar protein sorting 13 homolog B (VPS13B) gene by performing trio-based whole-exome sequencing (WES)
The 4-year-old female proband (III1, Figure 1) was the first child of the family born at 40 weeks gestation with a birth weight of 2,600 g from non-consanguineous, healthy parents

Summary

Introduction

Cohen syndrome (CS) (OMIM 216550), initially described in three patients by Cohen et al, is an uncommon autosomal recessive neurodevelopmental disorder with more than 200 causative mutations in ∼1,000 CS-affected individuals reported to date worldwide [1,2,3]. 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]. Cohen syndrome (CS) is a clinically heterogeneous disorder characterized by extensive phenotypic variation with autosomal recessive inheritance. 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

Objectives

Methods

Results

Conclusion