Lessons learned: next-generation sequencing applied to undiagnosed genetic diseases

Abstract

Rare genetic disorders, when considered together, are relatively common. Despite advancements in genetics and genomics technologies as well as increased understanding of genomic function and dysfunction, many genetic diseases continue to be difficult to diagnose. The goal of this Review is to increase the familiarity of genetic testing strategies for non-genetics providers. As genetic testing is increasingly used in primary care, many subspecialty clinics, and various inpatient settings, it is important that non-genetics providers have a fundamental understanding of the strengths and weaknesses of various genetic testing strategies as well as develop an ability to interpret genetic testing results. We provide background on commonly used genetic testing approaches, give examples of phenotypes in which the various genetic testing approaches are used, describe types of genetic and genomic variations, cover challenges in variant identification, provide examples in which next-generation sequencing (NGS) failed to uncover the variant responsible for a disease, and discuss opportunities for continued improvement in the application of NGS clinically. As genetic testing becomes increasingly a part of all areas of medicine, familiarity with genetic testing approaches and result interpretation is vital to decrease the burden of undiagnosed disease.

Figure 1. Schematic diagrams representing different types of genomic variation.

By column from left to right are diagrams depicting a gene schematic with a variant, the type of variant, and a specific example of that type of variant. Those columns are followed by example genes that have been demonstrated to harbor that kind of variant, a representative disease caused by that type of variant, and the OMIM reference for that disease. The last column additionally includes references to cases in this Review, if applicable.