Molecular diagnostic experience of whole-exome sequencing in adult patients

• Published in: Genetics in medicine Vol. 18; no. 7; pp. 678 - 685
• Main Authors: Posey, Jennifer E., Rosenfeld, Jill A., James, Regis A., Bainbridge, Matthew, Niu, Zhiyv, Wang, Xia, Dhar, Shweta, Wiszniewski, Wojciech, Akdemir, Zeynep H.C., Gambin, Tomasz, Xia, Fan, Person, Richard E., Walkiewicz, Magdalena, Shaw, Chad A., Sutton, V. Reid, Beaudet, Arthur L., Muzny, Donna, Eng, Christine M., Yang, Yaping, Gibbs, Richard A., Lupski, James R., Boerwinkle, Eric, Plon, Sharon E.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01-07-2016; Nature Publishing Group US; Elsevier Limited
• Subjects: 631/208/1516; 631/208/2489/144; 631/208/514/1948; Adult; adult patients; Biomedicine; Exome - genetics; Female; Genetic Diseases, Inborn - diagnosis; Genetic Diseases, Inborn - epidemiology; Genetic Predisposition to Disease; Genetic Testing; Genome, Human; High-Throughput Nucleotide Sequencing - methods; Human Genetics; Humans; Laboratory Medicine; Male; original-research-article; Pathology, Molecular - methods; whole-exome sequencing; whole-exome sequencing; adult patients
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/gim.2015.142

Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.
We performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.
Molecular diagnoses were reported for 17.5% (85/486) of adults, which is lower than that for a primarily pediatric population (25.2%; P = 0.0003); the diagnostic rate was higher (23.9%) for those 18–30 years of age compared to patients older than 30 years (10.4%; P = 0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses.
Early WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk, and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.