Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases

Genome Medicine

Arthur L. Beaudet¹  Shen Gu¹  Rajarshi Ghosh¹  Jennifer E. Posey¹  Richard A. Gibbs²  James R. Lupski³  Carlos A. Bacino⁴  Donna Muzny⁵  Theodore Chiang⁵  Avinash V. Dharmadhikari⁶  Francesco Vetrini⁶  Chunjing Qu⁶  Sami Al Masri⁶  Weimin He⁶  Rui Xiao⁷  Jennifer Scull⁷  Patricia Ward⁷  Alicia A. Braxton⁷  Pengfei Liu⁷  Chad A. Shaw⁷  Seema Lalani⁷  Yaping Yang⁷  Amy M. Breman⁷  Christine M. Eng⁷  Hongzheng Dai⁷  Janice L. Smith⁷  Ankita Patel⁷  Bo Yuan⁷  Linyan Meng⁷  Fan Xia⁷  Weimin Bi⁷  Sau-Wai Cheung⁷  Pawel Stankiewicz⁷  Xia Wang⁷  Allen H. Jiang⁸ 

[1]0000 0001 2160 926X, grid.39382.33, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 77030-3411, Houston, TX, USA

[2]0000 0001 2160 926X, grid.39382.33, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 77030-3411, Houston, TX, USA

[3]0000 0001 2160 926X, grid.39382.33, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

[4]0000 0001 2160 926X, grid.39382.33, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 77030-3411, Houston, TX, USA

[5]0000 0001 2160 926X, grid.39382.33, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

[6]0000 0001 2160 926X, grid.39382.33, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

[7]0000 0001 2200 2638, grid.416975.8, Texas Children’s Hospital, Houston, TX, USA

[8]0000 0001 2160 926X, grid.39382.33, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 77030-3411, Houston, TX, USA

[9]0000 0001 2200 2638, grid.416975.8, Texas Children’s Hospital, Houston, TX, USA

[10]0000 0001 2160 926X, grid.39382.33, Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

[11]Baylor Genetics Laboratories, Houston, TX, USA

[12]Baylor Genetics Laboratories, Houston, TX, USA

[13]0000 0001 2160 926X, grid.39382.33, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, 77030-3411, Houston, TX, USA

[14]Glenda Dawson High School, Pearland, TX, USA

关键词: Exome sequencing;    Microarray;    Structural variation;    Uniparental disomy;    ROH;    Dual molecular diagnoses;    Exonic CNV in AR disorders;   

DOI  :  10.1186/s13073-019-0639-5

来源: publisher

【 摘 要 】

BackgroundExome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.MethodsIn a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.ResultsThe QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.ConclusionsOur clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.

【 授权许可】

CC BY