Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing
Open accessAbstract
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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For complex phenotypes without a clear syndrome match, testing has moved toward early exome and genome sequencing.
“For more complex phenotypes–those without a clear match to a specific syndrome, such as neurodevelopmental disorders and multiple congenital anomalies–testing has gravitated towards early deployment of exome and genome-sequencing platforms that offer speedy resolution of what has historically often been a traumatic diagnostic odyssey15,134.”
From A brief history of human disease genetics (2020) · cites this paper as [134]
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- Authors
- Yang, Y., Muzny, D. M., 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, W. J., Bekheirnia, M. R., Stray-Pedersen, A., Liu, P., Wen, S., Alcaraz, W., Cui, H., Walkiewicz, M., Reid, J., Bainbridge, M., Patel, A., Boerwinkle, E., Beaudet, A. L., Lupski, J. R., Plon, S. E., Gibbs, R. A., & Eng, C. M.
- Affiliations
- Baylor College of Medicine (US)
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Corresponding author
- Eng, Christine M.
- ORCID
- Yang, Yaping
- Muzny, Donna M.
- Xia, Fan
- Niu, Zhiyv
- Person, Richard
- Ding, Yan
- Wang, Min
- Veeraraghavan, Narayanan
- Leduc, Magalie
- Zhang, Jing
- He, Weimin
- Scull, Jennifer
- Willis, Alecia
- Landsverk, Megan
- Bekheirnia, Mir Reza
- Liu, Pengfei
- Wen, Shu
- Cui, Hong
- Reid, Jeffrey
- Bainbridge, Matthew
- Patel, Ankita
- Boerwinkle, Eric
- Beaudet, Arthur L.
- Lupski, James R.
- Plon, Sharon E.
- Gibbs, Richard A.
- Eng, Christine M.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2014-11-12
- Volume
- 312
- Issue
- 18
- Pages
- 1870
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC4326249
- OpenAlex
- W2138956466
- Cited by
- 1,360
- References
- 29
- Citations by year
- 2026: 42 · 2025: 61 · 2024: 75 · 2023: 92 · 2022: 91 · 2021: 124 · 2020: 117 · 2019: 145 · 2018: 147 · 2017: 163 · 2016: 170 · 2015: 122 · 2014: 5 · 2013: 1 · 2012: 1
- FWCI
- 100.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Human Genome Research Institute (U54HG006542, U54HG003273, U01HG006485)
- National Institute of Diabetes and Digestive and Kidney Diseases (K12DK083014)
- National Institute of Neurological Disorders and Stroke (R01NS058529)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- genetic disorders, developmental delay, neurological phenotype, Mendelian inheritance, autosomal recessive disorder, X-linked disorders, uniparental disomy, incidental finding, FBN1 mutations, Marfan syndrome, pathogenic variants, pediatric patients, prenatal diagnosis
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Female, Fetus, Genetic Testing, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype, Referral and Consultation, Sequence Analysis, DNA, Genomics, Molecular Diagnostic Techniques, Genetic Diseases, Inborn, Incidental Findings, Exome
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