Abstract
Over the past decade, next-generation sequencing (NGS) has led to an exponential increase in our understanding of the genetic basis of Mendelian diseases. NGS allows for the analysis of multiple regions of the genome in one single reaction and has been shown to be a cost-effective and efficient tool in investigating patients with Mendelian diseases. More recently, NGS has been successfully deployed in the clinics, with a reported diagnostic yield of ~25 %. However, recommendations on clinical implementation of NGS are still evolving with numerous key challenges that impede the widespread use of genetics in everyday medicine. These challenges include when to order, on whom to order, what type of test to order, and how to interpret and communicate the results, including incidental findings, to the patient and family. In this review, we discuss these challenges and suggest guidelines on implementing NGS in the routine clinical workflow.
Highlights
Mendelian diseases, known as monogenic diseases, are disorders caused by mutations in one gene and include diseases like thalassemia, cystic fibrosis, among others
This allows for simultaneous interrogation of multiple genes through one single reaction and has been proven to be an effective alternative for establishing the genetic basic of Mendelian diseases in the research setting [8,9,10,11], and more recently, in the clinical setting [12,13,14,15,16]
Indications and clinical usefulness next-generation sequencing (NGS) is currently indicated for the detection of rare variants in patients with a phenotype suspected to be due to a Mendelian disease
Summary
Known as monogenic diseases, are disorders caused by mutations in one gene and include diseases like thalassemia, cystic fibrosis, among others. Besides offering a more comprehensive coverage of the “known” phenotype-specific genes, a targeted approach allows for deeper coverage of these genes compared to WES, which provides greater confidence in the variants detected. Laboratories that offer targeted testing may have expert knowledge for the given phenotype and may be in a better position to prioritize variants detected through NGS.
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