Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases

Journal of Medical Genetics
Jamie M EllingfordGraeme C M Black

Abstract

Diagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including CNVs. This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel NGS services for IRD. Three read-depth algorithms were applied to gene panel NGS data sets for 550 referred individuals, and informatics strategies used for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory. We confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques. Incorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic test...Continue Reading

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Citations

Sep 18, 2018·Expert Review of Molecular Diagnostics·Jayne Y Hehir-KwaPatrick Kemmeren
Jun 5, 2019·BMC Medical Genomics·Markus GulilatUte I Schwarz
Sep 1, 2020·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Kari BranhamK Thiran Jayasundera
May 31, 2018·Investigative Ophthalmology & Visual Science·Inmaculada Martin-MeridaCarmen Ayuso
Dec 15, 2019·European Journal of Human Genetics : EJHG·Omamah A JimanGraeme C Black
Feb 6, 2019·Scientific Reports·Cathrine JespersgaardKaren Grønskov
Jan 24, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Miriam BauwensElfride De Baere
Dec 14, 2018·Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology·Concetta ScimoneAntonina Sidoti
Feb 11, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Erin ZampaglioneKinga M Bujakowska
Aug 14, 2019·Acta Clinica Belgica·Mayssa AbdelwahedNeila Belguith
Nov 14, 2018·European Journal of Medical Genetics·Arnaud MolinMarie-Laure Kottler
May 11, 2021·Frontiers in Cell and Developmental Biology·Giulia AscariElfride De Baere
Jun 3, 2021·International Journal of Molecular Sciences·Adrian DockeryG Jane Farrar

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Methods Mentioned

BETA
gene panel
Illumina sequencing
PCR
RNA-seq

Software Mentioned

CASAVA
SAMtools
CoNVex
Canvas
Complete Genomics
Burrows Aligner
Manta
bedtools
ExomeDepth
CoNVaDING

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