Clinical molecular genetic testing is transforming personalized medicine and is appropriate for a range of applications, such as rare disease diagnostics and predictive testing for common disorders.
Whole-exome and whole-genome sequencing may become a first-line clinical test for some naive diagnostic cases, but classic genetic tests will continue to be used for the high analytical sensitivity of specific defects and for the confirmation of genome findings.
There remains no single test to detect the wide array of genetic defects that may be inherited or arise de novo; clinical diagnostics requires multiple approaches to determine a causal genetic defect.
Although genome sequencing may transform diagnostic approaches in large academic medical centres, access to expensive and sophisticated tests are not universal. Genetic testing must be available globally through validated simple technologies for molecular diagnostics (such as direct PCR, linkage analysis or multiplex ligation-dependent probe amplification).
The greatest challenge to clinical genomics is the reliable interpretation of the multiple and novel variants found through genome sequencing. Pathogenicity of genetic variants can be examined with bioinformatics prediction approaches, protein stability studies, transcriptional activity studies and allele- and/or gene-specific animal models.
As broader genomic information becomes available to providers and patients, partnerships will develop to convey patient-centred data, including incidental findings. The regulatory environment must adapt to the coming volume of genomic information to maximize benefit to patients and health-care systems and to match the expectations of the patient population with regard to these technologies.
Genomic technologies are reaching the point of being able to detect genetic variation in patients at high accuracy and reduced cost, offering the promise of fundamentally altering medicine. Still, although scientists and policy advisers grapple with how to interpret and how to handle the onslaught and ambiguity of genome-wide data, established and well-validated molecular technologies continue to have an important role, especially in regions of the world that have more limited access to next-generation sequencing capabilities. Here we review the range of methods currently available in a clinical setting as well as emerging approaches in clinical molecular diagnostics. In parallel, we outline implementation challenges that will be necessary to address to ensure the future of genetic medicine.
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The authors thank E. Davis and M. Angrist for their thoughtful suggestions for this manuscript.
The authors declare no competing financial interests.
- Large-insert clone
A large haplotype fragment that is inserted into, for example, a bacterial artificial chromosome.
- Oligonucleotide arrays
Hybridization of a nucleic acid sample to a very large set of oligonucleotide probes, which are attached to a solid support, to determine sequence, to detect variations or to carry out gene expression or mapping.
The collection of protein-coding regions (exons) in the genome. As exons comprise only 1% of the genome and contain the most easily understood and functionally relevant information, sequencing of only the exome is an efficient method of identifying many variants that are likely to affect a trait.
- Next-generation sequencing
(NGS). NGS platforms sequence as many as billions of DNA strands in parallel, yielding substantially more throughput than Sanger sequencing and minimizing the need for the fragment-cloning methods that are often used in Sanger sequencing of genomes.
- Direct genetic testing
Testing that looks at the presence or absence of known genetic variants that contribute to pathogenicity.
- Indirect genetic testing
Testing that compares the genetic regions of multiple affected persons to unaffected persons. Indirect genetic tests may evaluate patterns of inheritance in multiple family members with a known trait and look at the segregation of the trait with genetic markers.
- Linkage analysis
A statistical method for identifying a region of the genome that is implicated in a trait by observing which region is inherited from the parental strain carrying the trait in offspring that carry the trait.
- Single-nucleotide polymorphisms
(SNPs). Differences in the nucleotide composition at single positions in the DNA sequence.
- Short tandem repeats
(STRs). DNA sequences containing a variable number of highly polymorphic, tandemly repeated short (2–6 bp) sequences.
- Non-invasive prenatal testing
(NIPT). A method of obtaining a prenatal diagnosis by detecting fetal cells circulating in maternal blood.
- Pre-implantation genetic diagnosis
(PGD). An in vitro method of identifying genetic defects in in vitro fertilization embryos before maternal transfer and implant.
- Sanger sequencing
A method used to determine the nucleotides present in a fragment of DNA. It is based on the chain terminator method developed by Frederick Sanger but currently uses labelling of the chain terminator dideoxynucleotides, allowing sequencing in a single reaction.
- Array comparative genomic hybridization
(Array CGH). A microarray-based method of identifying differences in DNA copy number by comparing a sampled genome to a reference genome.
The proportion of individuals with a given genotype who display a particular phenotype.
- Fluorescent in situ hybridization
(FISH). A molecular and cytogenetic method using a fluorescently labelled DNA probe to detect a particular chromosome or gene using fluorescence microscopy.
- Uniparental disomy
(UPD). An occurrence of an individual inheriting both copies of her chromosome from one parent.
- Restriction fragment length polymorphisms
(RFLP). Variations between individuals in the lengths of DNA regions that are cut by a particular endonuclease.
- Multiplex ligation-dependent probe amplification
(MLPA). A molecular technique involving the ligation of two adjacent annealing oligonucleotides followed by quantitative PCR amplification of the ligated products, allowing the characterization of chromosomal aberrations in copy number or sequence and single-nucleotide polymorphism or mutation detection.
- Copy number variants
(CNVs). Structural genomic variants that result in copy number changes in specific chromosomal regions. Usually, there are two copies of each locus, but if, for example, duplications or triplications occur, then the number of copies will increase.
- Variants of unknown significance
(VUSs). Alterations in the sequence of a gene, the significance of which are unclear.
- Genetic determinism
The idea that genes and genetic variants are the primary factor determining and shaping human traits.
Describes a heritable effect on chromosome or gene function that is not accompanied by a change in DNA sequence but rather by modifications of chromatin or DNA.
An epigenetic variant of an allele. The activity of an epiallele is dependent on epigenetic modifications such as histone deacetylation or cytosine methylation.
- Genetic exceptionalism
The view that genetic information, traits and properties are qualitatively different and deserving of exceptional consideration.
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Katsanis, S., Katsanis, N. Molecular genetic testing and the future of clinical genomics. Nat Rev Genet 14, 415–426 (2013). https://doi.org/10.1038/nrg3493
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