Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders

Abstract

Purpose: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a first-tier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome- or genome-wide approach with a single test.

Methods: We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting.

Results: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of ~2% (ranging from 0 to -5.8% per disorder).

Conclusions: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.Genet Med advance online publication 27 October 2016.

Figure 1

Detection of clinically relevant CNVs in a cohort of broad genetic disorders. (a) The cohort screened for large copy-number variants (CNVs) consisting of 2,603 patients spanning 13 heterogeneous disorders, including neurodevelopmental disorders, deafness, blindness, renal disorders, metabolic disease, immunodeficiency, muscle disorders, craniofacial anomalies, sex dysmorphy, movement disorders, and hereditary cancers. (b) The number of patients for whom a conclusive diagnosis could be made based on a pathogenic CNV and the number of candidate CNVs identified per cohort.

Figure 2

Examples of the inheritance patterns of pathogenic copy-number variants. (a) A deletion of 22q11.21 is identified in a patient with neurodevelopmental delay. (b) A heterozygous 800-kb deletion encompassing a dominant gene (PAX2) explains the phenotype of a patient with a renal disorder. (c) A compound heterozygous event including a deletion of the first six exons of PANK2 (depicted in the lower left panel) in combination with a hemizygous frameshift mutation. c.1317del p.Arg440fs (NM_153638.2) reads with hemizygous mutation in exon 4 (depicted in lower right panel) in a patient with visual disturbances. (d) A homozygous deletion encompassing STRC results in a recessive disease pattern, explaining the deafness phenotype.