Critical assessment of variant prioritization methods for rare disease diagnosis within the Rare Genomes Project

全基因组测序 集合(抽象数据类型) 计算生物学 遗传学 基因组 生物 计算机科学 基因 程序设计语言
作者
Sarah L. Stenton,Melanie O’Leary,Gabrielle Lemire,Grace E. VanNoy,Stephanie DiTroia,Vijay Ganesh,Emily Groopman,Emily O’Heir,Brian E. Mangilog,Ikeoluwa A. Osei-Owusu,Lynn Pais,Jillian G. Serrano,Moriel Singer-Berk,Ben Weisburd,Michael W. Wilson,Christina Austin‐Tse,Marwa Abdelhakim,Azza Althagafi,Giulia Babbi,Riccardo Bellazzi,Samuele Bovo,Manolo Carta,Rita Casadio,Pieter-Jan Coenen,Federica De Paoli,Matteo Floris,Manavalan Gajapathy,Robert Hoehndorf,Julius O. B. Jacobsen,Thomas Joseph,Akash Kamandula,Panagiotis Katsonis,Cyrielle Kint,Olivier Lichtarge,Ivan Limongelli,Yulan Lu,Paolo Magni,Tarun Karthik Kumar Mamidi,Pier Luigi Martelli,M Mulargia,Giovanna Nicora,Keith Nykamp,Vikas Pejaver,Yisu Peng,Thang Pham,Maurizio S Podda,Aditya Rao,Ettore Rizzo,Vangala Govindakrishnan Saipradeep,Castrense Savojardo,Peter Schols,Yang Shen,Naveen Sivadasan,Damian Smedley,Dorian Soru,R. Srinivasan,Yuanfei Sun,Uma Sunderam,Wuwei Tan,Neelam Tiwari,Xiao Wang,Yaqiong Wang,Amanda Williams,Elizabeth A. Worthey,Rujie Yin,Yuning You,Daniel Zeiberg,Susanna Zucca,Constantina Bakolitsa,Steven E. Brenner,Stephanie M. Fullerton,Predrag Radivojac,Heidi L. Rehm,Anne O’Donnell-Luria
出处
期刊:Cold Spring Harbor Laboratory - medRxiv 被引量:1
标识
DOI:10.1101/2023.08.02.23293212
摘要

A major obstacle faced by rare disease families is obtaining a genetic diagnosis. The average "diagnostic odyssey" lasts over five years, and causal variants are identified in under 50%. The Rare Genomes Project (RGP) is a direct-to-participant research study on the utility of genome sequencing (GS) for diagnosis and gene discovery. Families are consented for sharing of sequence and phenotype data with researchers, allowing development of a Critical Assessment of Genome Interpretation (CAGI) community challenge, placing variant prioritization models head-to-head in a real-life clinical diagnostic setting.Predictors were provided a dataset of phenotype terms and variant calls from GS of 175 RGP individuals (65 families), including 35 solved training set families, with causal variants specified, and 30 test set families (14 solved, 16 unsolved). The challenge tasked teams with identifying the causal variants in as many test set families as possible. Ranked variant predictions were submitted with estimated probability of causal relationship (EPCR) values. Model performance was determined by two metrics, a weighted score based on rank position of true positive causal variants and maximum F-measure, based on precision and recall of causal variants across EPCR thresholds.Sixteen teams submitted predictions from 52 models, some with manual review incorporated. Top performing teams recalled the causal variants in up to 13 of 14 solved families by prioritizing high quality variant calls that were rare, predicted deleterious, segregating correctly, and consistent with reported phenotype. In unsolved families, newly discovered diagnostic variants were returned to two families following confirmatory RNA sequencing, and two prioritized novel disease gene candidates were entered into Matchmaker Exchange. In one example, RNA sequencing demonstrated aberrant splicing due to a deep intronic indel in ASNS, identified in trans with a frameshift variant, in an unsolved proband with phenotype overlap with asparagine synthetase deficiency.By objective assessment of variant predictions, we provide insights into current state-of-the-art algorithms and platforms for genome sequencing analysis for rare disease diagnosis and explore areas for future optimization. Identification of diagnostic variants in unsolved families promotes synergy between researchers with clinical and computational expertise as a means of advancing the field of clinical genome interpretation.
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