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UBC Theses and Dissertations

Exome sequencing for understanding phenotypic variability in subjects with 16p11.2 CNV Dastan, Jila


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 proband B may cause NDD phenotypes via a dominant-negative effect. In conclusion, pathogenic variants were identified in genes outside of the 16p11.2 region which could contribute to the clinical variability between parent-offspring dup16p11.2 carriers in this study. This suggests discordance in phenotype of dup16p11.2 carriers warrants further study by WES and individualized genetic assessment and counselling.

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