Clinical Whole Genome Sequencing

Next-generation whole-genome sequencing is increasingly being used in the clinical setting, and as costs continue to decline it may become a routine part of health care.  Early applications of the technology include solving undiagnosed genetic diseases, which may present as diagnostic dilemmas usually in children, or in the neonatal setting.  However, as the technology improves, whole-genome sequencing will likely subsume genetic testing for individual or even panels of genes, replacing individual genotyping assays with a comprehensive assessment of genetic variation.

Diagnostic Dilemmas

Whole genome and whole exome sequencing are increasingly being used in the clinic to aid in the diagnosis of rare congenital disorders and solve diagnostic dilemmas. One of the first and most high-profile examples of using clinical sequencing to end a diagnostic dilemmas is the case of 6 year old Nic Volker at the Medical College of Wisconsin, who suffered from a mysterious severe bowel disease of unknown origin. Searching for an explanation and treatment, doctors turned to next-generation DNA sequencing technology. They identified a mutation in the XIAP gene as the likely cause of his illness, knowledge that suggested a course of treatment that led to his recovery, ending his diagnostic oddessey. Read the case presentation (Identification of the X-linked Inhibitor of Apoptosis Protein mutation using WGS) and scientific publication in Genetics in Medicine (Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease).

Early results from some clinical sequencing programs estimate the success rate of disease gene identification at about 25-30%, offering hope to thousands of individuals with previously undiagnosed or untreated rare disorders, while recognizing that sequencing will not provide all of the answers.

Neonatal diagnostic sequencing

For newborns in the ICU, where time is critical, Stephen Kingsmore of Children's Mercy Hospital in Kansas City is working on a protocol to substantially reduce the turn-around time for obtaining sequencing results (Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units).  Through their Pediatric Genomic Medicine program they are offering STAT-Seq to help physicians make a rapid diagnosis in neonates who are acutely ill with a likely genetic disease.

View the webinar on STAT-Seq: Rapid WGS on the HiSeq® 2500 - Implications for a Neonatal Intensive Care Unit, (June, 2012), which describes 50-hour differential diagnosis of genetic disorders by whole genome sequencing (WGS), featuring substantially automated bioinformatic analysis. This is intended to be a prototype for deployment in neonatal intensive care units.


Duke Task Force For Neonatal Genomics

Duke University Medical Center is offering clinical sequencing for its pediatric patients through the Duke Task Force For Neonatal Genomics.

NIH Undiagnosed Disease Program (UDP)

The NIH UDP has two goals: To provide answers to patients with mysterious conditions that have long eluded diagnosis and to advance medical knowledge about rare and common diseases. Watch a CBS 60 minutes segment on the UDP, 'Investigating rare and tough diseases', broadcasted May 2012.

Rare Genomics Institute

A non-profit organization that gives families afflicted by rare genetic disorders access to genome sequencing and expert analysis. Find out more