Whole-Exome Sequencing Identifies Rare Inherited Diseases

Whole-exome sequencing (WES) could serve as a viable diagnostic approach for identifying rare inherited diseases and providing a resolution for patients on a diagnostic odyssey, which are patients with a suspected genetic condition for whom previous standard genetic testing did not reveal a cause.

WES is a laboratory process that determines, all at once, the entire unique DNA sequence, that is the inherited genetic material of an organism's genome. WES provides patients with rare genetic conditions who have been evaluated by multiple providers over, sometimes, years, without a diagnosis, an opportunity to get answers.


Scientists at the Mayo Clinic (Rochester, MN, USA) received requests for patients on a diagnostic odyssey. Seven of the cases were deferred, and 75 cases were approved to proceed with WES. Individualized Medicine Clinic genomic counselors met with 71 patients; 51 patients submitted specimens for clinical WES testing and received the results. This study took place from September 30, 2012, to March 30, 2014, and ultimately, 15 patients or 29% resulted in a diagnosis based on WES findings.

Peripheral blood was collected and DNA isolated from the proband and his or her affected and unaffected relatives. Some cases warranted the collection of fibroblasts via skin biopsy that were cultured before DNA extraction. DNA samples were submitted to one of three next-generation sequencing laboratories: Medical Genetics Laboratories (Baylor College of Medicine, Houston, TX, USA), Ambry Genetics (Aliso Viejo, CA, USA), and GeneDx (Gaithersburg, MD, USA).

Most patients who received WES testing 43/51 (84%) had undergone previous genetic testing during their diagnostic odyssey. Testing consisted of 29 chromosomal microarrays, 20 karyotyping, 30 metabolic testing and 39 candidate gene testing. Of the patients receiving candidate gene testing (single-gene or small panels), 22 were tested for one to five genes, and 12 patients were tested for six to 15 genes. In addition, five patients were tested with one to three independent single-gene tests and one large gene panel totaling 55 to 452 total genes tested per patient.

There were a total of 29 deleterious or likely deleterious variants found in 17 (33%) of the 51 cases. Incidental findings, reported only for the proband, include two medically actionable variants in disease genes MutY DNA Glycosylase (MUTYH) and Desmocollin 2 (DSC2) unrelated to the clinical phenotype. Three patients were identified as carriers for the known genetic diseases, cystic fibrosis, G6PD, and Fanconi anemia type C. Nine autosomal dominant, seven autosomal recessive, and one somatic disorder was identified. Two patients were found to have both a dominant and a recessive disorder.

Konstantinos Lazaridis, MD, director of the Mayo Individualized Medicine Clinic and primary investigator of the study, said, “The significant diagnostic yield, moderate cost and notable health marketplace acceptance of whole-exome sequencing for clinical purposes, compared with conventional genetic testing, make it a rational diagnostic approach for patients on a diagnostic odyssey. The success rate of 29%, which is about twofold higher than conventional genetic evaluations for such patients, makes WES a reasonable diagnostic approach for patients on a diagnostic odyssey.” The study was published in the March 2016 issue of the Mayo Clinic Proceedings.

Related Links:
Mayo Clinic
Baylor Medical Genetics Laboratories
Ambry Genetics