Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

Author:

Wojcik Monica HORCID,Lemire Gabrielle,Zaki Maha S,Wissman Mariel,Win Wathone,White Sue,Weisburd Ben,Waddell Leigh BORCID,Verboon Jeffrey M,VanNoy Grace E.,Töpf Ana,Tan Tiong YangORCID,Straub Volker,Stenton Sarah L,Snow Hana,Singer-Berk Moriel,Silver Josh,Shril Shirlee,Seaby Eleanor G,Schneider Ronen,Sankaran Vijay G,Sanchis-Juan Alba,Russell Kathryn A,Reinson Karit,Ravenscroft Gianina,Pierce Eric A,Place Emily M,Pajusalu Sander,Pais Lynn,Õunap KatrinORCID,Osei-Owusu Ikeoluwa,Okur Volkan,Oja Kaisa Teele,O’Leary Melanie,O’Heir Emily,Morel Chantal,Marchant Rhett GORCID,Mangilog Brian E,Madden Jill A,MacArthur Daniel,Lovgren Alysia,Lerner-Ellis Jordan P,Lin Jasmine,Laing Nigel,Hildebrandt Friedhelm,Groopman Emily,Goodrich Julia,Gleeson Joseph G,Ghaoui Roula,Genetti Casie A,Gazda Hanna T,Ganesh Vijay S.,Ganapathy Mythily,Gallacher LyndonORCID,Fu Jack,Evangelista Emily,England Eleina,Donkervoort Sandra,DiTroia Stephanie,Cooper Sandra TORCID,Chung Wendy K,Christodoulou JohnORCID,Chao Katherine R,Cato Liam D,Bujakowska Kinga M,Bryen Samantha JORCID,Brand Harrison,Bonnemann Carsten,Beggs Alan H,Baxter Samantha M,Agrawal Pankaj B,Talkowski Michael,Austin-Tse Chrissy,Rehm Heidi L,O’Donnell-Luria Anne

Abstract

AbstractBackgroundCausal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort.MethodsGS was performed for 744 individuals with rare disease who were genetically undiagnosed. Analysis included review of single nucleotide, indel, structural, and mitochondrial variants.ResultsWe successfully solved 218/744 (29.3%) cases using GS, with most solves involving established disease genes (157/218, 72.0%). Of all solved cases, 148 (67.9%) had previously had non-diagnostic ES. We systematically evaluated the 218 causal variants for features requiring GS to identify and 61/218 (28.0%) met these criteria, representing 8.2% of the entire cohort. These included small structural variants (13), copy neutral inversions and complex rearrangements (8), tandem repeat expansions (6), deep intronic variants (15), and coding variants that may be more easily found using GS related to uniformity of coverage (19).ConclusionWe describe the diagnostic yield of GS in a large and diverse cohort, illustrating several types of pathogenic variation eluding ES or other techniques. Our results reveal a higher diagnostic yield of GS, supporting the utility of a genome-first approach, with consideration of GS as a secondary or tertiary test when higher-resolution structural variant analysis is needed or there is a strong clinical suspicion for a condition and prior targeted genetic testing has been negative.

Publisher

Cold Spring Harbor Laboratory

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