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Exome sequencing identifies pathogenic variants of VPS13B in a patient with familial 16p11.2 duplication Dastan, Jila; Chijiwa, Chieko; Tang, Flamingo; Martell, Sally; Qiao, Ying; Rajcan-Separovic, Evica; Lewis, M. E S

Abstract

Background: The recurrent microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by incomplete penetrance and variable expressivity. This inter- and intra-familial clinical variability highlights the importance of personalized genetic counselling in individuals at-risk. Case presentation: In this study, we performed whole exome sequencing (WES) to look for other genomic alterations that could explain the clinical variability in a family with a boy presenting with NDD who inherited the dup16p11.2 from his apparently healthy mother. We identified novel splicing variants of VPS13B (8q22.2) in the proband with compound heterozygous inheritance. Two VPS13B mutations abolished the canonical splice sites resulting in low RNA expression in transformed lymphoblasts of the proband. VPS13B mutation causes Cohen syndrome (CS) consistent with the proband’s phenotype (intellectual disability (ID), microcephaly, facial gestalt, retinal dystrophy, joint hypermobility and neutropenia). The new diagnosis of CS has important health implication for the proband, provides the opportunity for more meaningful and accurate genetic counselling for the family; and underscores the importance of longitudinally following patients for evolving phenotypic features. Conclusions: This is the first report of a co-occurrence of pathogenic variants with familial dup16p11.2. Our finding suggests that the variable expressivity among carriers of rare putatively pathogenic CNVs such as dup16p11.2 warrants further study by WES and individualized genetic counselling of families with such CNVs.

Item Metadata

Title
Exome sequencing identifies pathogenic variants of VPS13B in a patient with familial 16p11.2 duplication
Creator
Dastan, Jila; Chijiwa, Chieko; Tang, Flamingo; Martell, Sally; Qiao, Ying; Rajcan-Separovic, Evica; Lewis, M. E S
Contributor
Children's Hospital (Vancouver, B.C.); Children's Hospital (Vancouver, B.C.). Research Institute
Publisher
BioMed Central
Date Issued
2016-11-10
Description
Background: The recurrent microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by incomplete penetrance and variable expressivity. This inter- and intra-familial clinical variability highlights the importance of personalized genetic counselling in individuals at-risk. Case presentation: In this study, we performed whole exome sequencing (WES) to look for other genomic alterations that could explain the clinical variability in a family with a boy presenting with NDD who inherited the dup16p11.2 from his apparently healthy mother. We identified novel splicing variants of VPS13B (8q22.2) in the proband with compound heterozygous inheritance. Two VPS13B mutations abolished the canonical splice sites resulting in low RNA expression in transformed lymphoblasts of the proband. VPS13B mutation causes Cohen syndrome (CS) consistent with the proband’s phenotype (intellectual disability (ID), microcephaly, facial gestalt, retinal dystrophy, joint hypermobility and neutropenia). The new diagnosis of CS has important health implication for the proband, provides the opportunity for more meaningful and accurate genetic counselling for the family; and underscores the importance of longitudinally following patients for evolving phenotypic features. Conclusions: This is the first report of a co-occurrence of pathogenic variants with familial dup16p11.2. Our finding suggests that the variable expressivity among carriers of rare putatively pathogenic CNVs such as dup16p11.2 warrants further study by WES and individualized genetic counselling of families with such CNVs.
Subject
16p11.2 duplication; Cohen syndrome; Neuro-developmental disorders; Variable expressivity; Whole exome sequencing; Case report
Genre
Article
Type
Text
Language
eng
Date Available
2017-12-14
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0362018
URI
http://hdl.handle.net/2429/64009
Affiliation
Medicine, Faculty of; Other UBC; Non UBC; Medical Genetics, Department of; Pathology and Laboratory Medicine, Department of
Citation
BMC Medical Genetics. 2016 Nov 10;17(1):78
Publisher DOI
10.1186/s12881-016-0340-0
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
The Author(s).
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)