Exome sequencing for understanding phenotypic variability in subjects with 16p11.2 CNV
department or school: Medicine, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Dastan, Jila
issued: 2016-10-31T00:00:00
issued: 2016
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by variable expressivity. I hypothesized that while some unique features reported in individuals with dup16p11.2 may be explained by the over-expression of its integral genes, co-occurrence of other genetic alterations in the genome may account for the variability in their clinical phenotypes. This hypothesis was explored in two unrelated subjects with NDD who each inherited the dup16p11.2 from an apparently healthy carrier parent. First, I performed a detailed phenotypic analysis of individuals with dup16p11.2 (published and current study). I did not find evidence of phenotypic commonality and consistent syndromic phenotype pattern among carriers of dup16p11.2. Next, I assessed the effect of dup16p11.2 on the expression of genes located within and nearby this region which showed that RNA expression of KCTD13, MAPK3 and MVP from 16p11.2 region was inconsistent in carriers of dup16p11.2. KTCD13 has been identified as a driver of a mirror brain phenotype of 16p11.2 CNV in zebrafish. However, the data presented here demonstrated that dup16p11.2 did not result in increased protein expression of KCTD13 in either probands or the healthy carrier parent, indicating that KCTD13 is not the sole cause of microcephaly in cases with dup16p11.2. Finally, whole exome sequencing (WES) was used to investigate the presence of genomic sequence changes in dup16p11.2 carriers that could explain such clinical variability. Compound heterozygous variants of VPS13B in proband A and missense variants of SYNE2 in proband B were identified. Mutations of VPS13B cause Cohen syndrome in keeping with proband A’s phenotype (ID, microcephaly, facial gestalt, retinal dystrophy, joint hypermobility and episodic neutropenia) and low RNA expression. The protein encoded by SYNE2, Nesprin 2, plays critical roles in neurogenesis in mice. Over-expression of Nesprin 2 identified in pr…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/57796
note: EXOME SEQUENCING FOR UNDERSTANDING PHENOTYPIC VARIABILITY IN SUBJECTS WITH 16p11.2 CNV by Jila Dastan M.D. Medicine, Shiraz University, 1993 M.Sc. Medical Genetics, Glasgow University, 1998 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Medical Genetics) The University of British Columbia (Vancouver) April 2016 © Jila Dastan, 2016 ii Abstract Microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by variable expressivity. I hypothesized that while some unique features reported in individuals with dup16p11.2 may be explained by the over-expression of its integral genes, co-occurrence of other genetic alterations in the genome may account for the variability in their clinical phenotypes. This hypothesis was explored in two unrelated subjects with NDD who each inherited the dup16p11.2 from an apparently healthy carrier parent. First, I performed a detailed phenotypic analysis of individuals with dup16p11.2 (published and current study). I did not find evidence of phenotypic commonality and consistent syndromic phenotype pattern among carriers of dup16p11.2. Next, I assessed the effect of dup16p11.2 on the expression of genes located within and nearby this region which showed that RNA expression of KCTD13, MAPK3 and MVP from 16p11.2 region was inconsistent in carriers of dup16p11.2. KTCD13 has been identified as a driver of a mirror brain phenotype of 16p11.2 CNV in zebrafish. However, the data presented here demonstrated that dup16p11.2 did not result in increased protein expression of KCTD13 in either probands or the healthy carrier parent, indicating that KCTD13 is not the sole cause of microcephaly in cases with dup16p11.2. Finally, whole exome sequencing (WES) was used to investigate the presence of genomic sequence changes in dup16p11.2 carriers that could explain such clinical variability…
has type: Thesis/Dissertation
date issued: 2016-05
is shown at: 10.14288/1.0300131
language: eng
degree discipline: Medical Genetics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/57796