A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative.
Exome sequencing
Genome sequencing
Phenotyping
Rare diseases
Undiagnosed diseases
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
26
01
2018
accepted:
09
04
2018
pubmed:
17
6
2018
medline:
13
3
2019
entrez:
17
6
2018
Statut:
ppublish
Résumé
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. 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. 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%). 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.
Identifiants
pubmed: 29907797
doi: 10.1038/s41436-018-0044-2
pii: S1098-3600(21)00106-4
pmc: PMC6295275
mid: NIHMS961141
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
161-172Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007672
Pays : United States
Investigateurs
David R Adams
(DR)
Mercedes E Alejandro
(ME)
Patrick Allard
(P)
Euan A Ashley
(EA)
Mahshid S Azamian
(MS)
Carlos A Bacino
(CA)
Ashok Balasubramanyam
(A)
Hayk Barseghyan
(H)
Gabriel F Batzli
(GF)
Alan H Beggs
(AH)
Babak Behnam
(B)
Hugo J Bellen
(HJ)
Jonathan A Bernstein
(JA)
Anna Bican
(A)
David P Bick
(DP)
Camille L Birch
(CL)
Devon Bonner
(D)
Braden E Boone
(BE)
Bret L Bostwick
(BL)
Lauren C Briere
(LC)
Donna M Brown
(DM)
Matthew Brush
(M)
Elizabeth A Burke
(EA)
Lindsay C Burrage
(LC)
Manish J Butte
(MJ)
Shan Chen
(S)
Gary D Clark
(GD)
Terra R Coakley
(TR)
Joy D Cogan
(JD)
Cynthia M Cooper
(CM)
Heidi Cope
(H)
William J Craigen
(WJ)
Precilla D'Souza
(P)
Mariska Davids
(M)
Jean M Davidson
(JM)
Jyoti G Dayal
(JG)
Esteban C Dell'Angelica
(EC)
Shweta U Dhar
(SU)
Katrina M Dipple
(KM)
Laurel A Donnell-Fink
(LA)
Naghmeh Dorrani
(N)
Daniel C Dorset
(DC)
Emilie D Douine
(ED)
David D Draper
(DD)
Annika M Dries
(AM)
David J Eckstein
(DJ)
Lisa T Emrick
(LT)
Christine M Eng
(CM)
Gregory M Enns
(GM)
Ascia Eskin
(A)
Cecilia Esteves
(C)
Tyra Estwick
(T)
Liliana Fernandez
(L)
Carlos Ferreira
(C)
Paul G Fisher
(PG)
Brent L Fogel
(BL)
Noah D Friedman
(ND)
William A Gahl
(WA)
Emily Glanton
(E)
Rena A Godfrey
(RA)
David B Goldstein
(DB)
Sarah E Gould
(SE)
Jean-Philippe F Gourdine
(JF)
Catherine A Groden
(CA)
Andrea L Gropman
(AL)
Melissa Haendel
(M)
Rizwan Hamid
(R)
Neil A Hanchard
(NA)
Lori H Handley
(LH)
Matthew R Herzog
(MR)
Ingrid A Holm
(IA)
Jason Hom
(J)
Ellen M Howerton
(EM)
Yong Huang
(Y)
Howard J Jacob
(HJ)
Mahim Jain
(M)
Yong-Hui Jiang
(YH)
Jean M Johnston
(JM)
Angela L Jones
(AL)
David M Koeller
(DM)
Isaac S Kohane
(IS)
Jennefer N Kohler
(JN)
Donna M Krasnewich
(DM)
Elizabeth L Krieg
(EL)
Joel B Krier
(JB)
Jennifer E Kyle
(JE)
Seema R Lalani
(SR)
C Christopher Lau
(CC)
Jozef Lazar
(J)
Kimberly LeBlanc
(K)
Brendan H Lee
(BH)
Hane Lee
(H)
Shawn E Levy
(SE)
Richard A Lewis
(RA)
Sharyn A Lincoln
(SA)
Sandra K Loo
(SK)
Joseph Loscalzo
(J)
Richard L Maas
(RL)
Ellen F Macnamara
(EF)
Calum A MacRae
(CA)
Valerie V Maduro
(VV)
Marta M Majcherska
(MM)
May Christine V Malicdan
(MCV)
Laura A Mamounas
(LA)
Teri A Manolio
(TA)
Thomas C Markello
(TC)
Ronit Marom
(R)
Martin G Martin
(MG)
Julian A Martínez-Agosto
(JA)
Shruti Marwaha
(S)
Thomas May
(T)
Allyn McConkie-Rosell
(A)
Colleen E McCormack
(CE)
Alexa T McCray
(AT)
Jason D Merker
(JD)
Thomas O Metz
(TO)
Matthew Might
(M)
Paolo M Moretti
(PM)
Marie Morimoto
(M)
John J Mulvihill
(JJ)
Jennifer L Murphy
(JL)
Donna M Muzny
(DM)
Michele E Nehrebecky
(ME)
Stan F Nelson
(SF)
J Scott Newberry
(JS)
John H Newman
(JH)
Sarah K Nicholas
(SK)
Donna Novacic
(D)
Jordan S Orange
(JS)
J Carl Pallais
(JC)
Christina Gs Palmer
(CG)
Jeanette C Papp
(JC)
Neil H Parker
(NH)
Loren Dm Pena
(LD)
John A Phillips
(JA)
Jennifer E Posey
(JE)
John H Postlethwait
(JH)
Lorraine Potocki
(L)
Barbara N Pusey
(BN)
Chloe M Reuter
(CM)
Amy K Robertson
(AK)
Lance H Rodan
(LH)
Jill A Rosenfeld
(JA)
Jacinda B Sampson
(JB)
Susan L Samson
(SL)
Kelly Schoch
(K)
Molly C Schroeder
(MC)
Daryl A Scott
(DA)
Prashant Sharma
(P)
Vandana Shashi
(V)
Edwin K Silverman
(EK)
Janet S Sinsheimer
(JS)
Kevin S Smith
(KS)
Rebecca C Spillmann
(RC)
Joan M Stoler
(JM)
Nicholas Stong
(N)
Jennifer A Sullivan
(JA)
David A Sweetser
(DA)
Queenie K-G Tan
(QK)
Cynthia J Tifft
(CJ)
Camilo Toro
(C)
Alyssa A Tran
(AA)
Tiina K Urv
(TK)
Zaheer M Valivullah
(ZM)
Eric Vilain
(E)
Tiphanie P Vogel
(TP)
Daryl M Waggott
(DM)
Colleen E Wahl
(CE)
Nicole M Walley
(NM)
Chris A Walsh
(CA)
Jijun Wan
(J)
Michael F Wangler
(MF)
Patricia A Ward
(PA)
Katrina M Waters
(KM)
Bobbie-Jo M Webb-Robertson
(BM)
Monte Westerfield
(M)
Matthew T Wheeler
(MT)
Anastasia L Wise
(AL)
Lynne A Wolfe
(LA)
Elizabeth A Worthey
(EA)
Shinya Yamamoto
(S)
Yaping Yang
(Y)
Amanda J Yoon
(AJ)
Guoyun Yu
(G)
Diane B Zastrow
(DB)
Chunli Zhao
(C)
Allison Zheng
(A)
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