Clinical whole-exome sequencing for the diagnosis of mendelian disorders

Yaping Yang, Donna M. Muzny, Jeffrey G. Reid, Matthew N. Bainbridge, Alecia Willis, Patricia A. Ward, Alicia Braxton, Joke Beuten, Fan Xia, Zhiyv Niu, Matthew Hardison, Richard Person, Mir Reza Bekheirnia, Magalie S. Leduc, Amelia Kirby, Peter Pham, Jennifer Scull, Min Wang, Yan Ding, Sharon E. Plon & 4 others James R. Lupski, Arthur L. Beaudet, Richard A. Gibbs, Christine M. Eng

Research output: Contribution to journalArticle

967 Citations (Scopus)

Abstract

BACKGROUND: Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. METHODS: We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. RESULTS: We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. CONCLUSIONS: Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition.

Original languageEnglish (US)
Pages (from-to)1502-1511
Number of pages10
JournalNew England Journal of Medicine
Volume369
Issue number16
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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Exome
Phenotype
Alleles
X-Linked Genes
Inborn Genetic Diseases
Insurance Coverage
Molecular Pathology
Computational Biology
Nervous System
Genes
Physical Examination
History
Confidence Intervals
Physicians
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yang, Y., Muzny, D. M., Reid, J. G., Bainbridge, M. N., Willis, A., Ward, P. A., ... Eng, C. M. (2013). Clinical whole-exome sequencing for the diagnosis of mendelian disorders. New England Journal of Medicine, 369(16), 1502-1511. https://doi.org/10.1056/NEJMoa1306555

Clinical whole-exome sequencing for the diagnosis of mendelian disorders. / Yang, Yaping; Muzny, Donna M.; Reid, Jeffrey G.; Bainbridge, Matthew N.; Willis, Alecia; Ward, Patricia A.; Braxton, Alicia; Beuten, Joke; Xia, Fan; Niu, Zhiyv; Hardison, Matthew; Person, Richard; Bekheirnia, Mir Reza; Leduc, Magalie S.; Kirby, Amelia; Pham, Peter; Scull, Jennifer; Wang, Min; Ding, Yan; Plon, Sharon E.; Lupski, James R.; Beaudet, Arthur L.; Gibbs, Richard A.; Eng, Christine M.

In: New England Journal of Medicine, Vol. 369, No. 16, 01.01.2013, p. 1502-1511.

Research output: Contribution to journalArticle

Yang, Y, Muzny, DM, Reid, JG, Bainbridge, MN, Willis, A, Ward, PA, Braxton, A, Beuten, J, Xia, F, Niu, Z, Hardison, M, Person, R, Bekheirnia, MR, Leduc, MS, Kirby, A, Pham, P, Scull, J, Wang, M, Ding, Y, Plon, SE, Lupski, JR, Beaudet, AL, Gibbs, RA & Eng, CM 2013, 'Clinical whole-exome sequencing for the diagnosis of mendelian disorders', New England Journal of Medicine, vol. 369, no. 16, pp. 1502-1511. https://doi.org/10.1056/NEJMoa1306555
Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. New England Journal of Medicine. 2013 Jan 1;369(16):1502-1511. https://doi.org/10.1056/NEJMoa1306555
Yang, Yaping ; Muzny, Donna M. ; Reid, Jeffrey G. ; Bainbridge, Matthew N. ; Willis, Alecia ; Ward, Patricia A. ; Braxton, Alicia ; Beuten, Joke ; Xia, Fan ; Niu, Zhiyv ; Hardison, Matthew ; Person, Richard ; Bekheirnia, Mir Reza ; Leduc, Magalie S. ; Kirby, Amelia ; Pham, Peter ; Scull, Jennifer ; Wang, Min ; Ding, Yan ; Plon, Sharon E. ; Lupski, James R. ; Beaudet, Arthur L. ; Gibbs, Richard A. ; Eng, Christine M. / Clinical whole-exome sequencing for the diagnosis of mendelian disorders. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 16. pp. 1502-1511.
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AU - Yang, Yaping

AU - Muzny, Donna M.

AU - Reid, Jeffrey G.

AU - Bainbridge, Matthew N.

AU - Willis, Alecia

AU - Ward, Patricia A.

AU - Braxton, Alicia

AU - Beuten, Joke

AU - Xia, Fan

AU - Niu, Zhiyv

AU - Hardison, Matthew

AU - Person, Richard

AU - Bekheirnia, Mir Reza

AU - Leduc, Magalie S.

AU - Kirby, Amelia

AU - Pham, Peter

AU - Scull, Jennifer

AU - Wang, Min

AU - Ding, Yan

AU - Plon, Sharon E.

AU - Lupski, James R.

AU - Beaudet, Arthur L.

AU - Gibbs, Richard A.

AU - Eng, Christine M.

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N2 - BACKGROUND: Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. METHODS: We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. RESULTS: We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. CONCLUSIONS: Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition.

AB - BACKGROUND: Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. METHODS: We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. RESULTS: We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. CONCLUSIONS: Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition.

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