Dataset Information

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders.

ABSTRACT: Background: Both whole exome sequencing and copy number variants sequencing were applied to identify the genetic cause of rare pediatric disorders. In our study, we aimed to investigate the diagnostic yield of parallel tests of trio whole exome sequencing and copy number variants sequencing and its clinical utility. Methods: After collecting detailed clinical information, a total of 60 patients were referred to parallel tests of whole exome sequencing and copy number variants sequencing, which used shared initial libraries. Results: 26 pathogenic or likely pathogenic single nucleotide variants and 11 copy number variants were identified in 32 patients. 65.4% (17/26) of the SNVs were novel. The overall diagnosis rate was 53.3%. For the patients with positive results, 22 (36.7%) patients were diagnosed by whole exome sequencing and 10 (16.7%) patients were diagnosed by copy number variants sequencing. We also reviewed clinical impact on selected cases. Conclusion: We adopted an approach by performing parallel tests of trio whole exome sequencing and copy number variants sequencing with shared initial libraries. This strategy is relatively efficient and cost-effective for the diagnosis of rare pediatric disorders with high heterogeneity.

SUBMITTER: Hu X

PROVIDER: S-EPMC7300249 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders.

Hu Xuyun X Guo Ruolan R Guo Jun J Qi Zhan Z Li Wei W Hao Chanjuan C

Frontiers in genetics 20200611

<b>Background:</b> Both whole exome sequencing and copy number variants sequencing were applied to identify the genetic cause of rare pediatric disorders. In our study, we aimed to investigate the diagnostic yield of parallel tests of trio whole exome sequencing and copy number variants sequencing and its clinical utility. <b>Methods:</b> After collecting detailed clinical information, a total of 60 patients were referred to parallel tests of whole exome sequencing and copy number variants seque ...[more]

PMID: 32595695

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Project description:Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

Project description:BackgroundExome sequencing (ES) is a first-tier diagnostic test for many suspected Mendelian disorders. While it is routine to detect small sequence variants, it is not a standard practice in clinical settings to detect germline copy-number variants (CNVs) from ES data due to several reasons relating to performance. In this work, we comprehensively characterized one of the most sensitive ES-based CNV tools, ExomeDepth, against SNP array, a standard of care test in clinical settings to detect genome-wide CNVs.MethodsWe propose a modified ExomeDepth workflow by excluding exons with low mappability prior to variant calling to drastically reduce the false positives originating from the repetitive regions of the genome, and an iterative variant calling framework to assess the reproducibility. We used a cohort of 307 individuals with clinical ES data and clinical SNP array to estimate the sensitivity and false discovery rate of the CNV detection using exome sequencing. Further, we performed targeted testing of the STRC gene in 1972 individuals. To reduce the number of variants for downstream analysis, we performed a large-scale iterative variant calling process with random control cohorts to assess the reproducibility of the CNVs.ResultsThe modified workflow presented in this paper reduced the number of total variants identified by one third while retaining a higher sensitivity of 97% and resulted in an improved false discovery rate of 11.4% compared to the default ExomeDepth pipeline. The exclusion of exons with low mappability removes 4.5% of the exons, including a subset of exons (0.6%) in disease-associated genes which are intractable by short-read next-generation sequencing (NGS). Results from the reproducibility analysis showed that the clinically reported variants were reproducible 100% of the time and that the modified workflow can be used to rank variants from high to low confidence. Targeted testing of 30 CNVs identified in STRC, a challenging gene to ascertain by NGS, showed a 100% validation rate.ConclusionsIn summary, we introduced a modification to the default ExomeDepth workflow to reduce the false positives originating from the repetitive regions of the genome, created a large-scale iterative variant calling framework for reproducibility, and provided recommendations for implementation in clinical settings.

Dataset Information

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders.

Publications

Parallel Tests of Whole Exome Sequencing and Copy Number Variant Sequencing Increase the Diagnosis Yields of Rare Pediatric Disorders.

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