Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases

Author:

Pagnamenta Alistair T.,Camps Carme,Giacopuzzi Edoardo,Taylor John M.,Hashim Mona,Calpena Eduardo,Kaisaki Pamela J.,Hashimoto Akiko,Yu Jing,Sanders Edward,Schwessinger Ron,Hughes Jim R.,Lunter Gerton,Dreau Helene,Ferla Matteo,Lange Lukas,Kesim Yesim,Ragoussis Vassilis,Vavoulis Dimitrios V.,Allroggen Holger,Ansorge Olaf,Babbs Christian,Banka Siddharth,Baños-Piñero Benito,Beeson David,Ben-Ami Tal,Bennett David L.,Bento Celeste,Blair Edward,Brasch-Andersen Charlotte,Bull Katherine R.,Cario Holger,Cilliers Deirdre,Conti Valerio,Davies E. Graham,Dhalla Fatima,Dacal Beatriz Diez,Dong Yin,Dunford James E.,Guerrini Renzo,Harris Adrian L.,Hartley Jane,Hollander Georg,Javaid Kassim,Kane Maureen,Kelly Deirdre,Kelly Dominic,Knight Samantha J. L.,Kreins Alexandra Y.,Kvikstad Erika M.,Langman Craig B.,Lester Tracy,Lines Kate E.,Lord Simon R.,Lu Xin,Mansour Sahar,Manzur Adnan,Maroofian Reza,Marsden Brian,Mason Joanne,McGowan Simon J.,Mei Davide,Mlcochova Hana,Murakami Yoshiko,Németh Andrea H.,Okoli Steven,Ormondroyd Elizabeth,Ousager Lilian Bomme,Palace Jacqueline,Patel Smita Y.,Pentony Melissa M.,Pugh Chris,Rad Aboulfazl,Ramesh Archana,Riva Simone G.,Roberts Irene,Roy Noémi,Salminen Outi,Schilling Kyleen D.,Scott Caroline,Sen Arjune,Smith Conrad,Stevenson Mark,Thakker Rajesh V.,Twigg Stephen R. F.,Uhlig Holm H.,van Wijk Richard,Vona Barbara,Wall Steven,Wang Jing,Watkins Hugh,Zak Jaroslav,Schuh Anna H.,Kini Usha,Wilkie Andrew O. M.,Popitsch Niko,Taylor Jenny C.ORCID

Abstract

Abstract Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. Methods We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. Results Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. Conclusions Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

Funder

NIHR Oxford Biomedical Research Centre

VTCT Foundation

Wellcome

NIHR Great Ormond Street Hospital Biomedical Research Centre

NIHR Academic Clinical Lectureship & Academy of Medical Sciences Starter Grant for Clinical Lecturers

MRC Core funding

Wellcome Trust Strategic Award

Wellcome Trust

Oxford Experimental Cancer Medicine Centre

MRC Core Funding

NIHR Rare Diseases Translational Research Collaboration

Gilead

Oxford Craniofacial Unit

OUH NHS Foundation Trust

WIMM Strategic Alliance

Great Ormond Street Charity and the MRC

Cancer Research Institute/Irvington postdoctoral fellowship

Health Research (NIHR) Oxford Biomedical Research Centre

Leona M. and Harry B. Helmsley Charitable Trust

Action Medical Research

MRC

Medical Research Council

German Research Foundation

Intramural funding (fortüne), University of Tübingen

Ministry of Science, Research and Art Baden-Württemberg

Regione Toscana

Fondazione Cassa di Risparmio di Firenze

Publisher

Springer Science and Business Media LLC

Subject

Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine

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