Annotating DNA variants is the next major goal for human genetics

Abstract

Clinical genetic testing has undergone a dramatic transformation in the past two decades. Diagnostic laboratories that previously tested for well-established disease-causing DNA variants in a handful of genes have evolved into sequencing factories identifying thousands of variants of known and unknown medical consequence. Sorting out what does and does not cause disease in our genomes is the next great challenge in making genetics a central feature of healthcare. I propose that closing the gap in our ability to interpret variation responsible for Mendelian disorders provides a grand and unprecedented opportunity for geneticists. Human geneticists are well placed to coordinate a systematic evaluation of variants in collaboration with basic scientists and clinicians. Sharing of knowledge, data, methods, and tools will aid both researchers and healthcare workers in achieving their common goal of defining the pathogenic potential of variants. Generation of variant annotations will inform genetic testing and will deepen our understanding of gene and protein function, thereby aiding the search for molecular targeted therapies.

Figure 1

Allelic Heterogeneity as Represented by the Distribution of the Number of Variants Reported per Gene in the LOVD Variants from the Leiden Open Variation Database (LOVD) version 2.0–24 or higher and with properly configured reference sequences were used for extracting the number of unique alleles reported per gene. If a gene was present in multiple databases (duplicate instances), the raw data were parsed such that the highest number of variants per a given gene was reported. Variants per gene were binned into multiples of ten when there were <500 and multiples of 50 when there were ≥500. Data are courtesy of Ivo F.A.C. Fokkema and Johan T. den Dunnen (personal communication).

Figure 2

An Illustration of the Growing Gap in Our Understanding of the Clinical Implications of DNA Variants over Time As the cost of sequencing declines, the total number of variants identified is expected to grow dramatically (MassGenomics). Annotated variants represent only a fraction of the total number of variants identified. Over time, the proportion of annotated variants is not expected to increase at the same rate as the discovery of rare variants, causing an ever increasing “interpretive gap.”