TY - JOUR
T1 - Molecular findings among patients referred for clinical whole-exome sequencing
AU - Yang, Yaping
AU - Muzny, Donna M.
AU - Xia, Fan
AU - Niu, Zhiyv
AU - Person, Richard
AU - Ding, Yan
AU - Ward, Patricia
AU - Braxton, Alicia
AU - Wang, Min
AU - Buhay, Christian
AU - Veeraraghavan, Narayanan
AU - Hawes, Alicia
AU - Chiang, Theodore
AU - Leduc, Magalie
AU - Beuten, Joke
AU - Zhang, Jing
AU - He, Weimin
AU - Scull, Jennifer
AU - Willis, Alecia
AU - Landsverk, Megan
AU - Craigen, William J.
AU - Bekheirnia, Mir Reza
AU - Stray-Pedersen, Asbjorg
AU - Liu, Pengfei
AU - Wen, Shu
AU - Alcaraz, Wendy
AU - Cui, Hong
AU - Walkiewicz, Magdalena
AU - Reid, Jeffrey
AU - Bainbridge, Matthew
AU - Patel, Ankita
AU - Boerwinkle, Eric
AU - Beaudet, Arthur L.
AU - Lupski, James R.
AU - Plon, Sharon E.
AU - Gibbs, Richard A.
AU - Eng, Christine M.
N1 - Publisher Copyright:
Copyright 2014 American Medical Association. All rights reserved.
PY - 2014/11/12
Y1 - 2014/11/12
N2 - IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. RESULTS: A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95%CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95%CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95%CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95%CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
AB - IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. RESULTS: A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95%CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95%CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95%CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95%CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
UR - http://www.scopus.com/inward/record.url?scp=84918771753&partnerID=8YFLogxK
U2 - 10.1001/jama.2014.14601
DO - 10.1001/jama.2014.14601
M3 - Article
C2 - 25326635
AN - SCOPUS:84918771753
SN - 0098-7484
VL - 312
SP - 1870
EP - 1879
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 18
ER -