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Abstract
Background Despite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%–20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES.
Methods This study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed.
Results On the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure.
Conclusion Combining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.
- genetic variation
- high-throughput nucleotide sequencing
- molecular diagnostic techniques
- congenital, hereditary, and neonatal diseases and abnormalities
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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- genetic variation
- high-throughput nucleotide sequencing
- molecular diagnostic techniques
- congenital, hereditary, and neonatal diseases and abnormalities
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Footnotes
QT and XV are joint first authors.
QT and XV contributed equally.
Contributors QT and XV wrote the manuscript. JT, LR and J-FT designed the study and revised the manuscript. KY, M-EN, GV, FR, BD, VM, SB, DG, VG, CW, MW, CC, LP, RD, AT, BH, FV, IH, RT, BC, WD, TB, OP, BL, LM, AD, TB, CM, VS, CC, TC and RH contributed to patient ascertainment and medical data management. All authors have read and approved the final manuscript. JT and J-FT are guarantors.
Funding This study was partially subsidised by ANRT (CIFRE grant) and by MIAI@Grenoble Alpes (ANR-19-P3IA-0003).
Competing interests QT, XV, LR and J-FT are employed by Eurofins Biomnis, a private medical biology laboratory. KY is employed by Seqone Genomics a private bioinformatics software provider.
Provenance and peer review Not commissioned; externally peer reviewed.
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