Settling the score: variant prioritization and Mendelian disease

Abstract

When investigating Mendelian disease using exome or genome sequencing, distinguishing disease-causing genetic variants from the multitude of candidate variants is a complex, multidimensional task. Many prioritization tools and online interpretation resources exist, and professional organizations have offered clinical guidelines for review and return of prioritization results. In this Review, we describe the strengths and weaknesses of widely used computational approaches, explain their roles in the diagnostic and discovery process and discuss how they can inform (and misinform) expert reviewers. We place variant prioritization in the wider context of gene prioritization, burden testing and genotype–phenotype association, and we discuss opportunities and challenges introduced by whole-genome sequencing.

Genome sequencing for rightward hemispheric language dominance

“…Whole genome sequence data, of the type produced in the present study, also contain information on noncoding variation. Rare noncoding variation has recently been implicated in neurodevelopmental disorders such as autism, and a significant fraction of this variation is potentially important for gene function and regulation . The noncoding genome comprises 98% of the genome, and interpreting the variation within these regions is challenging.…”

“…These ranking approaches include CADD, DANN, GWAVA, M‐CAP, MetaSVM or REVEL . However, these ranking approaches are not very concordant with each other . Moreover, the methods rely on assumptions about the deleteriousness/pathogenicity of variants, so that the overall approach is not an obvious fit for a non‐pathogenic trait such as RHLD.…”

Clinical sequencing: From raw data to diagnosis with lifetime value

“…For the prioritization of CNVs, their size and population frequency (eg, DGV) can be used. However, prioritization scores and predicted variant effects should never be automatically associated with pathogenicity, requiring manual expert review and intepretation …”

Measuring “Intolerance to Mutation” in Human Genetics

“…In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, it is useful to know whether a single disrupting mutation in a gene is likely to be deleterious [1][2][3][4] . With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large numbers of healthy individuals-genes that appear intolerant to mutation 3,5-9 .…”