@article{7be3365189284dcb96a6df7d72760ba8,
title = "A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative",
abstract = "Purpose: Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. Methods: In 38 ES negative patients an individualized genomic–phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred. Results: Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). Conclusions: Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.",
keywords = "Exome sequencing, Genome sequencing, Phenotyping, Rare diseases, Undiagnosed diseases",
author = "{Undiagnosed Diseases Network} and Vandana Shashi and Kelly Schoch and Rebecca Spillmann and Heidi Cope and Tan, {Queenie K.G.} and Nicole Walley and Loren Pena and Allyn McConkie-Rosell and Jiang, {Yong Hui} and Nicholas Stong and Need, {Anna C.} and Goldstein, {David B.} and Adams, {David R.} and Alejandro, {Mercedes E.} and Patrick Allard and Ashley, {Euan A.} and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Ashok Balasubramanyam and Hayk Barseghyan and Batzli, {Gabriel F.} and Beggs, {Alan H.} and Babak Behnam and Bellen, {Hugo J.} and Bernstein, {Jonathan A.} and Anna Bican and Bick, {David P.} and Birch, {Camille L.} and Devon Bonner and Boone, {Braden E.} and Bostwick, {Bret L.} and Briere, {Lauren C.} and Brown, {Donna M.} and Matthew Brush and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Butte, {Manish J.} and Shan Chen and Clark, {Gary D.} and Coakley, {Terra R.} and Cogan, {Joy D.} and Cooper, {Cynthia M.} and Heidi Cope and Craigen, {William J.} and Precilla D{\textquoteright}Souza and Mariska Davids and Davidson, {Jean M.} and Dayal, {Jyoti G.} and Melissa Haendel and Koeller, {David M.}",
note = "Funding Information: This work has received support by the National Institutes of Health (NIH) Common Fund through the Office of Strategic Coordination/Office of the NIH Director (U01HG007672, to Shashi V and Goldstein DB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2018, American College of Medical Genetics and Genomics.",
year = "2019",
month = jan,
day = "1",
doi = "10.1038/s41436-018-0044-2",
language = "English (US)",
volume = "21",
pages = "161--172",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",
number = "1",
}