Interpretation and consequences of copy number variants

  • George Burghel

Student thesis: Unknown


Abstract Background: Copy Number Variants (CNVs) are an important cause for human diseases. The overall aim of this DClinSci research project was to improve the classification and understanding of the impact of CNVs. Objectives: (1) Current approaches to clinical interpretation leave a significant proportion of CNVs with uncertain clinical significance (class 3). Periodic re-analysis of all Class 3 CNVs in a diagnostic laboratory is not feasible. We decided to devise a strategy to facilitate large-scale re-analysis for a sub-group of class 3 CNVs. (2) Socioeconomic status (SES) is a major determinant of health and related outcomes. Biological factors including genetic variants that may influence SES are only beginning to be understood. We decided to study the correlation between pathogenic CNVs and SES. Methods and Results: We curated a large database of CNVs identified at the Manchester Centre of Genomic Medicine over a period of ~7 years via array comparative genomic hybridisation performed in ~16,000 patients. We harmonised clinical class terminology as per current guidance and identified ~7,000 Class 3 CNVs. From these CNVs we chose to systematically re-analyse 2,173 class 3 losses (CNLs). Then using a gene-focussed approach, with up-to-date disease association information and haploinsufficiency scores we generated a shortlist of 204 class 3 CNLs that encompassed gene(s) with autosomal dominant disease association predicted to be haploinsufficient or have a loss of function disease mechanism. Clinical scientist manual review of these shortlisted CNLs led to reclassification of 13 class 3 CNLs (~6.4% of the shortlisted cohort) as (likely)pathogenic. We then performed a detailed in silico analyses of a single case with class 3 16p13.3 CNL and showed that haploinsufficiency of ATP6V0C probably underlies the pathology of this condition. We studied the Index of Multiple Deprivation Rank (IMDR) of 473 individuals with (likely)pathogenic autosomal CNVs and known inheritance status. The IMDR distribution of families with (likely)pathogenic CNVs was significantly different from the general population. Families with inherited CNVs were significantly more likely to be living in areas of higher deprivation when compared with families that had individuals with de novo CNVs. Conclusions: We present an efficient re-analysis strategy for Class 3 CNLs for diagnostic laboratories. Although the value of re-analysis of next generation sequencing data is well established, this is the first such study of CNV re-analysis. Our study on correlations between pathogenic CNVs and SES provide unique insights into biological determinants of SES. As pathogenic CNVs are relatively frequent in the general population, these results have important medical and policy consequences.
Date of Award1 Aug 2021
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorSiddharth Banka (Supervisor)


  • Variants of Uncertain Significance
  • reclassification
  • ATP6V0C
  • CNV
  • Socioeconomic Status

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