Genomic Diagnosis for Pediatric Disorders: Revolution and Evolution

Abstract

Powerful, recent advances in technologies to analyze the genome have had a profound impact on the practice of medical genetics, both in the laboratory and in the clinic. Increasing utilization of genome-wide testing such as chromosomal microarray analysis and exome sequencing have lead a shift toward a "genotype-first" approach. Numerous techniques are now available to diagnose a particular syndrome or phenotype, and while traditional techniques remain efficient tools in certain situations, higher-throughput technologies have become the de facto laboratory tool for diagnosis of most conditions. However, selecting the right assay or technology is challenging, and the wrong choice may lead to prolonged time to diagnosis, or even a missed diagnosis. In this review, we will discuss current core technologies for the diagnosis of classic genetic disorders to shed light on the benefits and disadvantages of these strategies, including diagnostic efficiency, variant interpretation, and secondary findings. Finally, we review upcoming technologies posed to impart further changes in the field of genetic diagnostics as we move toward "genome-first" practice.

Keywords: copy number variants; genetic syndromes; genetics; genomic diagnostics; next-generation sequencing; pediatrics; sequencing.

Figure 1

Diagnostic technologies and applications. (A) General considerations used in determining the appropriate technology used for diagnosis. Choosing the appropriate technique is a multi-factorial process, depending on reason for study, clinical presentation and associated genetic heterogeneity, molecular mechanisms, time and cost considerations, among others, and there is often no single “right” approach. (B–E) Common clinical diagnostic workflows for various genetic syndromes. See clinical examples in text for more detail.