Prevalence and Properties of Intragenic Copy-number Variation in Mendelian Disease Genes

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2018 Jun 14

PMID 29895855

Citations 86

Authors

Rebecca Truty

Joshua Paul

Michael Kennemer

Stephen E Lincoln

Eric Olivares

Robert L Nussbaum

Swaroop Aradhya

Affiliations

Soon will be listed here.

Abstract

Purpose: We investigated the frequencies and characteristics of intragenic copy-number variants (CNVs) in a deep sampling of disease genes associated with monogenic disorders.

Methods: Subsets of 1507 genes were tested using next-generation sequencing to simultaneously detect sequence variants and CNVs in >143,000 individuals referred for genetic testing. We analyzed CNVs in gene panels for hereditary cancer syndromes and cardiovascular, neurological, or pediatric disorders.

Results: Our analysis identified 2844 intragenic CNVs in 384 clinically tested genes. CNVs were observed in 1.9% of the entire cohort but in a disproportionately high fraction (9.8%) of individuals with a clinically significant result. CNVs accounted for 4.7-35% of pathogenic variants, depending on clinical specialty. Distinct patterns existed among CNVs in terms of copy number, location, exons affected, clinical classification, and genes affected. Separately, analysis of de-identified data for 599 genes unrelated to the clinical phenotype yielded 4054 CNVs. Most of these CNVs were novel rare events, present as duplications, and enriched in genes associated with recessive disorders or lacking loss-of-function mutational mechanisms.

Conclusion: Universal intragenic CNV analysis adds substantial clinical sensitivity to genetic testing. Clinically relevant CNVs have distinct properties that distinguish them from CNVs contributing to normal variation in human disease genes.

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References

Pfundt R, Del Rosario M, Vissers L, Kwint M, Janssen I, de Leeuw N . Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. Genet Med. 2017; 19(6):667-675. PMC: 5460076. DOI: 10.1038/gim.2016.163. View

Retterer K, Scuffins J, Schmidt D, Lewis R, Pineda-Alvarez D, Stafford A . Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort. Genet Med. 2014; 17(8):623-9. DOI: 10.1038/gim.2014.160. View

Aradhya S, Lewis R, Bonaga T, Nwokekeh N, Stafford A, Boggs B . Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders. Genet Med. 2012; 14(6):594-603. DOI: 10.1038/gim.2011.65. View

Gambin T, Yuan B, Bi W, Liu P, Rosenfeld J, Coban-Akdemir Z . Identification of novel candidate disease genes from de novo exonic copy number variants. Genome Med. 2017; 9(1):83. PMC: 5607840. DOI: 10.1186/s13073-017-0472-7. View

Dhami P, Coffey A, Abbs S, Vermeesch J, Dumanski J, Woodward K . Exon array CGH: detection of copy-number changes at the resolution of individual exons in the human genome. Am J Hum Genet. 2005; 76(5):750-62. PMC: 1199365. DOI: 10.1086/429588. View

Hehir-Kwa J, Pfundt R, Veltman J . Exome sequencing and whole genome sequencing for the detection of copy number variation. Expert Rev Mol Diagn. 2015; 15(8):1023-32. DOI: 10.1586/14737159.2015.1053467. View

Johansson L, van Dijk F, de Boer E, van Dijk-Bos K, Jongbloed J, van der Hout A . CoNVaDING: Single Exon Variation Detection in Targeted NGS Data. Hum Mutat. 2016; 37(5):457-64. DOI: 10.1002/humu.22969. View

Chen Y, Zhao L, Wang Y, Cao M, Gelowani V, Xu M . SeqCNV: a novel method for identification of copy number variations in targeted next-generation sequencing data. BMC Bioinformatics. 2017; 18(1):147. PMC: 5335817. DOI: 10.1186/s12859-017-1566-3. View

Lincoln S, Kobayashi Y, Anderson M, Yang S, Desmond A, Mills M . A Systematic Comparison of Traditional and Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Genes in More Than 1000 Patients. J Mol Diagn. 2015; 17(5):533-44. DOI: 10.1016/j.jmoldx.2015.04.009. View

10.

Lek M, Karczewski K, Minikel E, Samocha K, Banks E, Fennell T . Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016; 536(7616):285-91. PMC: 5018207. DOI: 10.1038/nature19057. View

11.

Sudmant P, Rausch T, Gardner E, Handsaker R, Abyzov A, Huddleston J . An integrated map of structural variation in 2,504 human genomes. Nature. 2015; 526(7571):75-81. PMC: 4617611. DOI: 10.1038/nature15394. View

12.

Mills R, Walter K, Stewart C, Handsaker R, Chen K, Alkan C . Mapping copy number variation by population-scale genome sequencing. Nature. 2011; 470(7332):59-65. PMC: 3077050. DOI: 10.1038/nature09708. View

13.

Landrum M, Lee J, Benson M, Brown G, Chao C, Chitipiralla S . ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2015; 44(D1):D862-8. PMC: 4702865. DOI: 10.1093/nar/gkv1222. View

14.

Zarrei M, MacDonald J, Merico D, Scherer S . A copy number variation map of the human genome. Nat Rev Genet. 2015; 16(3):172-83. DOI: 10.1038/nrg3871. View

15.

Kurian A, Hare E, Mills M, Kingham K, McPherson L, Whittemore A . Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014; 32(19):2001-9. PMC: 4067941. DOI: 10.1200/JCO.2013.53.6607. View

16.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. PMC: 4544753. DOI: 10.1038/gim.2015.30. View

17.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho Y . Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med. 2017; 19(10):1105-1117. PMC: 5632818. DOI: 10.1038/gim.2017.37. View

18.

Newman S, Hermetz K, Weckselblatt B, Rudd M . Next-generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. Am J Hum Genet. 2015; 96(2):208-20. PMC: 4320257. DOI: 10.1016/j.ajhg.2014.12.017. View

19.

Judkins T, Rosenthal E, Arnell C, Burbidge L, Geary W, Barrus T . Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer. 2012; 118(21):5210-6. PMC: 3532625. DOI: 10.1002/cncr.27556. View

20.

Green R, Berg J, Grody W, Kalia S, Korf B, Martin C . ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-74. PMC: 3727274. DOI: 10.1038/gim.2013.73. View