Rapid diagnostic genome sequencing for genetic diseases in inpatients: an emerging new standard-of-care

Abstract

Over 7,300 single locus (Mendelian) genetic diseases have a known molecular cause. While individually rare, collectively these diseases have a prevalence of at least 2% and are a leading cause of infant mortality in high income countries. More than 500 genetic diseases have effective treatments. Unfortunately, genetic diseases are often still mis-diagnosed and mis-treated as common conditions or go undiagnosed for years. First described in 2012, phenotype-guided genome sequencing is emerging as the gold standard for diagnosis of Mendelian disease.1 For acutely ill inpatients, rapid genome sequencing can provide a molecular diagnosis (or rule out suspected genetic disorders) in a day.2 From 2012 to 2021, 31 clinical studies documented the diagnostic and clinical utility of rapid genome or exome sequencing in acutely ill children.3 Several studies in different healthcare systems have shown that rapid genome sequencing is cost-effective as a first-tier test in children with suspected genetic diseases who are receiving intensive care, and provision of rapid diagnostic genome sequencing is becoming policy in this population in several countries. Early diagnosis is enabling early implementation of precision therapy. The impact of the latter on the natural history of genetic diseases is starting to become evident.