Beyond Gene Panels: Whole Exome Sequencing for Diagnosis of Congenital Heart Disease.

Abstract

Listen

Translate article

See Article by Szot and Cuny et al Driven by next-generation sequencing, rapid advances in our knowledge of inherited cardiovascular diseases have greatly improved our ability to make molecular diagnoses. Focused gene panels covering select sets of genes implicated in a specific disease are the mainstay of clinical genetic testing. Panel testing has proven to be successful in the diagnosis and management of Mendelian diseases attributable to a single gene such as cystic fibrosis or a limited number of genes as in the case of several cardiomyopathies, channelopathies, and connective tissue disorders. Although gene panels have diagnostic rates surpassing 70% for some inherited cardiovascular diseases, the utility of gene panels has not translated as effectively to the detection of diseases characterized by more complex genetic architecture such as congenital heart disease (CHD). CHD, a heterogeneous group of structural cardiac malformations, is the most common human birth defect and the leading cause of neonatal death because of a congenital illness.1 Hundreds of genes have been identified as having confirmed or putative pathogenicity in causing syndromic and nonsyndromic CHD.2,3 For familial, nonsyndromic cases of CHD, the diagnosis rate for gene panels inclusive of >50 CHD-associated genes is 31% to 46% at best,4,5 a far cry from the diagnosis rate of 75% achieved by a 17-gene panel for long QT syndrome.6 Moreover, the diagnostic yield for nonfamilial (sporadic), nonsyndromic CHD is even slimmer. Although ≈20% of the genetic attributable risk for sporadic CHD has been uncovered to date,7 the genetic cause of the vast majority …