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.
Highlights
Tools for genomic diagnosis have evolved rapidly over the past two decades, resulting in remarkably improved diagnostic rates as well as a significant increase in the number of disease genes
Genomic diagnostic testing for pediatric disorders has transformed from low resolution and single locus (e.g., Sanger, fluorescence in situ hybridization (FISH), PCR) analyses to high-throughput and high resolution genome-wide testing (e.g., chromosomal microarrays (CMA), Exome Sequencing (ES), genome sequencing (GS)), with an-ever diminishing distinction between cytogenetic and molecular genetics (Table 6)
The widespread adoption of these methods has led to challenges in how to rapidly and accurately interpret the staggering number of single nucleotide and copy number variants that exist in the human genome
Summary
Tools for genomic diagnosis have evolved rapidly over the past two decades, resulting in remarkably improved diagnostic rates as well as a significant increase in the number of disease genes. The scope of identifiable mutations ranges from changes in the amount of a particular genomic locus, such as loss or gain of entire chromosomes (i.e., aneuploidy) or smaller regions of DNA (i.e., copy number variants, CNVs), to changes in the structure of the genome (i.e., translocations, inversions, insertions), and to changes in the sequence of the genome (i.e., single nucleotide variants and short insertions/deletions) These advances have had a profound impact on how we diagnose patients who present with clinical features of known genetic disorders. Imprinting disorders such as Prader-Willi Syndrome possible simultaneously, resulting in targeted panels including only a few or up to hundreds of genes, as well as examination of the entire exome [i.e., the protein coding regions of the genome, see section Exome Sequencing (ES)] or genome These improvements allow a streamlined approach to diagnosis of genetic disorders, by avoiding unnecessary evaluations and diagnostic studies such as Ophthalmology and Cardiology evaluations for hearing loss patients or functional studies for patients with Fanconi anemia or Osteogenesis Imperfecta. Critical regions: - Cat-like cry: 1.5 Mb region of 5p15.31 - Speech delay: 3 Mb region of 5p15.33-5p15.32. - Dysmorphic facial features: 2.4 Mb region of 5p15.31-p15.2
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