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CNV analysis using whole exome sequencing identified biallelic CNVs of VPS13B in siblings with intellectual disability.

Authors
  • Enomoto, Yumi1
  • Tsurusaki, Yoshinori1
  • Yokoi, Takayuki2
  • Abe-Hatano, Chihiro2
  • Ida, Kazumi2
  • Naruto, Takuya1
  • Mitsui, Jun3
  • Tsuji, Shoji3
  • Morishita, Shinichi4
  • Kurosawa, Kenji5
  • 1 Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan. , (Japan)
  • 2 Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan. , (Japan)
  • 3 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. , (Japan)
  • 4 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. , (Japan)
  • 5 Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan; Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan. Electronic address: [email protected] , (Japan)
Type
Published Article
Journal
European journal of medical genetics
Publication Date
Jan 01, 2020
Volume
63
Issue
1
Pages
103610–103610
Identifiers
DOI: 10.1016/j.ejmg.2018.12.015
PMID: 30602132
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Cohen syndrome is an autosomal recessive disease characterized by myopia, retinal dystrophy, neutropenia, short stature, microcephaly, persistent hypotonia, intellectual disability (ID), and a distinct facial appearance. Cohen syndrome is caused by mutations, such as single nucleotide variants (SNVs) and small insertions/deletions, and copy number variations (CNVs) in vacuolar protein sorting 13 homolog B (VPS13B). Here, we report Japanese siblings with ID, who were subsequently diagnosed with Cohen syndrome by whole exome sequencing (WES). The older sister had hypotonia and mild to moderate ID. The younger sister had short stature, postnatal onset microcephaly, and developmental delay. No pathogenic mutations, including SNVs or small insertions/deletions, were found by WES. Comparative genomic hybridization (CGH)-array did not detect pathogenic copy-number variations. However, using log2-ratio values calculated from WES depth data, we detected pathogenic biallelic heterozygous CNVs in VPS13B in both sisters: a maternally-derived exons 8-15 deletion and a paternally-derived exons 32-33 deletion. Interestingly, the sisters did not show obvious clinical features suggestive of Cohen syndrome, including the distinct facial appearance. These results support the idea that the typical facial features of Cohen syndrome do not appear in early childhood, and that the late appearance of distinctive clinical features results in delayed diagnosis. Furthermore, these results show the possibility that CNV analysis using log2-ratio values calculated from WES depth data is a useful and effective method to detect CNVs, such as the deletion of multiple exons. Copyright © 2019 Elsevier Masson SAS. All rights reserved.

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