Research ArticlesDiagnostics

Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units

Science Translational Medicine  03 Oct 2012:
Vol. 4, Issue 154, pp. 154ra135
DOI: 10.1126/scitranslmed.3004041

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Speed Heals

The waiting might not be the hardest part for families receiving a diagnosis in neonatal intensive care units (NICUs), but it can be destructive nonetheless. While they wait on pins and needles for their newborn baby’s diagnosis, parents anguish, nurture false hope, wrestle with feelings of guilt—and all the while, treatment and counseling are delayed. Now, Saunders et al. describe a method that uses whole-genome sequencing (WGS) to achieve a differential diagnosis of genetic disorders in 50 hours rather than the 4 to 6 weeks.

Many of the ~3,500 genetic diseases of known cause manifest symptoms during the first 28 days of life, but full clinical symptoms might not be evident in newborns. Genetic screens performed on newborns are rapid, but are designed to unearth only a few genetic disorders, and serial gene sequencing is too slow to be clinically useful. Together, these complicating factors lead to the administration of treatments based on nonspecific or obscure symptoms, which can be unhelpful or dangerous. Often, either death or release from the hospital occurs before the diagnosis is made.

The new WGS protocol cuts analysis time by using automated bioinformatic analysis. Using their newly developed protocol, the authors performed retrospective 50-hour WGS to confirm, in two children, known molecular diagnoses that had been made using other methods. Next, prospective WGS revealed a molecular diagnosis of a BRAT1-related syndrome in one newborn; identified the causative mutation in a baby with epidermolysis bullosa; ruled out the presence of defects in candidate genes in a third infants; and, in a pedigree, pinpointed BCL9L as a new recessive gene (HTX6) that gives rise to visceral heterotaxy—the abnormal arrangement of organs in the chest and abdominal cavities. WGS of parents or affected siblings helped to speed up the identification of disease genes in the prospective cases. These findings strengthen the notion that WGS can shorten the differential diagnosis process and quicken to move toward targeted treatment and genetic and prognostic counseling. The authors note that the speed and cost of WGS continues to rise and fall, respectively. However, fast WGS is clinically useful when coupled with fast and affordable methods of analysis.