Background
The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts.
Methods
We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups.
Results
We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants.
Conclusions
These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms.
Sex chromosomes are the basis of sexual differentiation during embryonic development. Variations of the traditional XX or XY karyotype may result in conditions where the genotype is discordant with the phenotype. Detection of these conditions in the past typically occurred during adolescence, due to delayed puberty, or during adulthood, due to infertility. With the increasing availability of non-invasive prenatal testing and high-resolution ultrasound, more cases of genotype-phenotype sex discordance are being identified in routine clinical practice during early pregnancy. These discordant results present significant diagnostic and counselling challenges, and their potential should be included in increasingly complex pre-NIPT counselling.
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