Clinical Application of Whole-exome Sequencing Across Clinical Indications

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2015 Dec 4

PMID 26633542

Citations 465

Authors

Kyle Retterer

Jane Juusola

Megan T Cho

Patrik Vitazka

Francisca Millan

Federica Gibellini

Annette Vertino-Bell

Nizar Smaoui

Julie Neidich

Kristin G Monaghan

Dianalee McKnight

Renkui Bai

Sharon Suchy

Bethany Friedman

Jackie Tahiliani

Daniel Pineda-Alvarez

Gabriele Richard

Tracy Brandt

Eden Haverfield

Wendy K Chung

Sherri Bale

Affiliations

Soon will be listed here.

Abstract

Purpose: We report the diagnostic yield of whole-exome sequencing (WES) in 3,040 consecutive cases at a single clinical laboratory.

Methods: WES was performed for many different clinical indications and included the proband plus two or more family members in 76% of cases.

Results: The overall diagnostic yield of WES was 28.8%. The diagnostic yield was 23.6% in proband-only cases and 31.0% when three family members were analyzed. The highest yield was for patients who had disorders involving hearing (55%, N = 11), vision (47%, N = 60), the skeletal muscle system (40%, N = 43), the skeletal system (39%, N = 54), multiple congenital anomalies (36%, N = 729), skin (32%, N = 31), the central nervous system (31%, N = 1,082), and the cardiovascular system (28%, N = 54). Of 2,091 cases in which secondary findings were analyzed for 56 American College of Medical Genetics and Genomics-recommended genes, 6.2% (N = 129) had reportable pathogenic variants. In addition to cases with a definitive diagnosis, in 24.2% of cases a candidate gene was reported that may later be reclassified as being associated with a definitive diagnosis.

Conclusion: Our experience with our first 3,040 WES cases suggests that analysis of trios significantly improves the diagnostic yield compared with proband-only testing for genetically heterogeneous disorders and facilitates identification of novel candidate genes.Genet Med 18 7, 696-704.

Citing Articles

Variants in , encoding the presynaptic protein Bassoon, result in a novel neurodevelopmental disorder with a broad phenotypic range.

Guzman S, Ruggiero S, Ganesan S, Ellis C, Harrison A, Sullivan K medRxiv. 2025; .

PMID: 39990563 PMC: 11844618. DOI: 10.1101/2025.02.10.25321755.

Community-oriented, hospital level genetics: a new approach to improve access for underserved communities.

Gofin Y, Tibi F, Fanous E, Ben-Shachar S, Sukenik-Halevy R Pediatr Res. 2025; .

PMID: 39972153 DOI: 10.1038/s41390-025-03908-2.

Inactivation of CaV1 and CaV2 channels.

Limpitikul W, Dick I J Gen Physiol. 2025; 157(2).

PMID: 39883005 PMC: 11781272. DOI: 10.1085/jgp.202313531.

Prevalence of Pathogenic Variants and Eligibility Criteria for Genetic Testing in Patients Who Visit a Memory Clinic.

van der Lee S, Hulsman M, Van Spaendonk R, Van Der Schaar J, Dijkstra J, Tesi N Neurology. 2025; 104(4):e210273.

PMID: 39869842 PMC: 11776143. DOI: 10.1212/WNL.0000000000210273.

Variants in the SOX9 transactivation middle domain induce axial skeleton dysplasia and scoliosis.

Wang L, Liu Z, Zhao S, Xu K, Aceves V, Qiu C Proc Natl Acad Sci U S A. 2025; 122(4):e2313978121.

PMID: 39854231 PMC: 11789016. DOI: 10.1073/pnas.2313978121.

References

Gregor A, Oti M, Kouwenhoven E, Hoyer J, Sticht H, Ekici A . De novo mutations in the genome organizer CTCF cause intellectual disability. Am J Hum Genet. 2013; 93(1):124-31. PMC: 3710752. DOI: 10.1016/j.ajhg.2013.05.007. View

Allen A, Cossette P, Delanty N, Eichler E, Goldstein D, Han Y . De novo mutations in epileptic encephalopathies. Nature. 2013; 501(7466):217-21. PMC: 3773011. DOI: 10.1038/nature12439. View

Bronicki L, Redin C, Drunat S, Piton A, Lyons M, Passemard S . Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A. Eur J Hum Genet. 2015; 23(11):1482-7. PMC: 4613470. DOI: 10.1038/ejhg.2015.29. View

Tham E, Lindstrand A, Santani A, Malmgren H, Nesbitt A, Dubbs H . Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features. Am J Hum Genet. 2015; 96(3):507-13. PMC: 4375419. DOI: 10.1016/j.ajhg.2015.01.016. View

Cushion T, Paciorkowski A, Pilz D, Mullins J, Seltzer L, Marion R . De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. Am J Hum Genet. 2014; 94(4):634-41. PMC: 3980418. DOI: 10.1016/j.ajhg.2014.03.009. View

Zhang W, Cui H, Wong L . Comprehensive one-step molecular analyses of mitochondrial genome by massively parallel sequencing. Clin Chem. 2012; 58(9):1322-31. DOI: 10.1373/clinchem.2011.181438. View

Li H . A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011; 27(21):2987-93. PMC: 3198575. DOI: 10.1093/bioinformatics/btr509. View

Xue Y, Ankala A, Wilcox W, Hegde M . Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2014; 17(6):444-51. DOI: 10.1038/gim.2014.122. View

Stenson P, Mort M, Ball E, Shaw K, Phillips A, Cooper D . The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2013; 133(1):1-9. PMC: 3898141. DOI: 10.1007/s00439-013-1358-4. View

10.

Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton J . De novo mutations in histone-modifying genes in congenital heart disease. Nature. 2013; 498(7453):220-3. PMC: 3706629. DOI: 10.1038/nature12141. View

11.

Van der Auwera G, Carneiro M, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A . From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2014; 43:11.10.1-11.10.33. PMC: 4243306. DOI: 10.1002/0471250953.bi1110s43. View

12.

Iossifov I, ORoak B, Sanders S, Ronemus M, Krumm N, Levy D . The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014; 515(7526):216-21. PMC: 4313871. DOI: 10.1038/nature13908. View

13.

Haack T, Hogarth P, Kruer M, Gregory A, Wieland T, Schwarzmayr T . Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet. 2012; 91(6):1144-9. PMC: 3516593. DOI: 10.1016/j.ajhg.2012.10.019. View

14.

Kohler S, Doelken S, Mungall C, Bauer S, Firth H, Bailleul-Forestier I . The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Res. 2013; 42(Database issue):D966-74. PMC: 3965098. DOI: 10.1093/nar/gkt1026. View

15.

Yang Y, Muzny D, Xia F, Niu Z, Person R, Ding Y . Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014; 312(18):1870-9. PMC: 4326249. DOI: 10.1001/jama.2014.14601. View

16.

Ruzzo E, Capo-Chichi J, Ben-Zeev B, Chitayat D, Mao H, Pappas A . Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy. Neuron. 2013; 80(2):429-41. PMC: 3820368. DOI: 10.1016/j.neuron.2013.08.013. View

17.

Shang L, Cho M, Retterer K, Folk L, Humberson J, Rohena L . Mutations in ARID2 are associated with intellectual disabilities. Neurogenetics. 2015; 16(4):307-14. DOI: 10.1007/s10048-015-0454-0. View

18.

Lalani S, Zhang J, Schaaf C, Brown C, Magoulas P, Chun-Hui Tsai A . Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am J Hum Genet. 2014; 95(5):579-83. PMC: 4225583. DOI: 10.1016/j.ajhg.2014.09.014. View

19.

Bai R, Wong L . Detection and quantification of heteroplasmic mutant mitochondrial DNA by real-time amplification refractory mutation system quantitative PCR analysis: a single-step approach. Clin Chem. 2004; 50(6):996-1001. DOI: 10.1373/clinchem.2004.031153. View

20.

Xia F, Bainbridge M, Tan T, Wangler M, Scheuerle A, Zackai E . De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea. Am J Hum Genet. 2014; 94(5):784-9. PMC: 4067559. DOI: 10.1016/j.ajhg.2014.04.006. View