Molecular findings among patients referred for clinical whole-exome sequencing

Yaping Yang, Donna M. Muzny, Fan Xia, Zhiyv Niu, Richard Person, Yan Ding, Patricia Ward, Alicia Braxton, Min Wang, Christian Buhay, Narayanan Veeraraghavan, Alicia Hawes, Theodore Chiang, Magalie Leduc, Joke Beuten, Jing Zhang, Weimin He, Jennifer Scull, Alecia Willis, Megan Landsverk & 17 others William J. Craigen, Mir Reza Bekheirnia, Asbjorg Stray-Pedersen, Pengfei Liu, Shu Wen, Wendy Alcaraz, Hong Cui, Magdalena Walkiewicz, Jeffrey Reid, Matthew Bainbridge, Ankita Patel, Eric Boerwinkle, Arthur L. Beaudet, James R. Lupski, Sharon E. Plon, Richard A. Gibbs, Christine M. Eng

Research output: Contribution to journalArticle

619 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1870-1879
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume312
Issue number18
DOIs
StatePublished - Nov 12 2014
Externally publishedYes

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Exome
Incidental Findings
Mutation
Inborn Genetic Diseases
Genomics
Genes
Phenotype
Marfan Syndrome
Molecular Pathology
Medical Genetics
Nervous System
Observational Studies
Fetus

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Molecular findings among patients referred for clinical whole-exome sequencing. / Yang, Yaping; Muzny, Donna M.; Xia, Fan; Niu, Zhiyv; Person, Richard; Ding, Yan; Ward, Patricia; Braxton, Alicia; Wang, Min; Buhay, Christian; Veeraraghavan, Narayanan; Hawes, Alicia; Chiang, Theodore; Leduc, Magalie; Beuten, Joke; Zhang, Jing; He, Weimin; Scull, Jennifer; Willis, Alecia; Landsverk, Megan; Craigen, William J.; Bekheirnia, Mir Reza; Stray-Pedersen, Asbjorg; Liu, Pengfei; Wen, Shu; Alcaraz, Wendy; Cui, Hong; Walkiewicz, Magdalena; Reid, Jeffrey; Bainbridge, Matthew; Patel, Ankita; Boerwinkle, Eric; Beaudet, Arthur L.; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.

In: JAMA - Journal of the American Medical Association, Vol. 312, No. 18, 12.11.2014, p. 1870-1879.

Research output: Contribution to journalArticle

Yang, Y, Muzny, DM, Xia, F, Niu, Z, Person, R, Ding, Y, Ward, P, Braxton, A, Wang, M, Buhay, C, Veeraraghavan, N, Hawes, A, Chiang, T, Leduc, M, Beuten, J, Zhang, J, He, W, Scull, J, Willis, A, Landsverk, M, Craigen, WJ, Bekheirnia, MR, Stray-Pedersen, A, Liu, P, Wen, S, Alcaraz, W, Cui, H, Walkiewicz, M, Reid, J, Bainbridge, M, Patel, A, Boerwinkle, E, Beaudet, AL, Lupski, JR, Plon, SE, Gibbs, RA & Eng, CM 2014, 'Molecular findings among patients referred for clinical whole-exome sequencing', JAMA - Journal of the American Medical Association, vol. 312, no. 18, pp. 1870-1879. https://doi.org/10.1001/jama.2014.14601
Yang, Yaping ; Muzny, Donna M. ; Xia, Fan ; Niu, Zhiyv ; Person, Richard ; Ding, Yan ; Ward, Patricia ; Braxton, Alicia ; Wang, Min ; Buhay, Christian ; Veeraraghavan, Narayanan ; Hawes, Alicia ; Chiang, Theodore ; Leduc, Magalie ; Beuten, Joke ; Zhang, Jing ; He, Weimin ; Scull, Jennifer ; Willis, Alecia ; Landsverk, Megan ; Craigen, William J. ; Bekheirnia, Mir Reza ; Stray-Pedersen, Asbjorg ; Liu, Pengfei ; Wen, Shu ; Alcaraz, Wendy ; Cui, Hong ; Walkiewicz, Magdalena ; Reid, Jeffrey ; Bainbridge, Matthew ; Patel, Ankita ; Boerwinkle, Eric ; Beaudet, Arthur L. ; Lupski, James R. ; Plon, Sharon E. ; Gibbs, Richard A. ; Eng, Christine M. / Molecular findings among patients referred for clinical whole-exome sequencing. In: JAMA - Journal of the American Medical Association. 2014 ; Vol. 312, No. 18. pp. 1870-1879.
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title = "Molecular findings among patients referred for clinical whole-exome sequencing",
abstract = "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.",
author = "Yaping Yang and Muzny, {Donna M.} and Fan Xia and Zhiyv Niu and Richard Person and Yan Ding and Patricia Ward and Alicia Braxton and Min Wang and Christian Buhay and Narayanan Veeraraghavan and Alicia Hawes and Theodore Chiang and Magalie Leduc and Joke Beuten and Jing Zhang and Weimin He and Jennifer Scull and Alecia Willis and Megan Landsverk and Craigen, {William J.} and Bekheirnia, {Mir Reza} and Asbjorg Stray-Pedersen and Pengfei Liu and Shu Wen and Wendy Alcaraz and Hong Cui and Magdalena Walkiewicz and Jeffrey Reid and Matthew Bainbridge and Ankita Patel and Eric Boerwinkle and Beaudet, {Arthur L.} and Lupski, {James R.} and Plon, {Sharon E.} and Gibbs, {Richard A.} and Eng, {Christine M.}",
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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.

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.

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