The human pangenome and the flavor of epilepsy variant interpretation

Reference. Today, the human pangenome was announced, the first reference of the human genome that systematically includes a cohort of genetically diverse individuals. The human genome, once thought to be a linear reference, is now a graph with nodes and edges. I came across the pangenome publications when I was thinking about a comment that I made earlier this week, when I was asked whether people on our team have their own flavor of variant interpretation. Let me share with you how both topics connect. Continue reading

Why variants of uncertain significance need explanatoriness

ACMG. Imagine the following scenario: you identify a de novo variant in SCN1A in a young child with the typical clinical features of Dravet Syndrome. However, the lab returns the variant as a variant of uncertain significance. The variant is a missense variant that has never been seen before and the lab argues that they are simply applying the current variant classification criteria. Certainly, either the lab is wrong or the variant classification criteria are deficient. Shouldn’t this variant be a pathogenic variant? Your patient clearly has the typical clinical features that are very unlikely explained by anything but the de novo SCN1A variant. In fact, both assumptions are incorrect, but it is important to know the background. Here is a blog post on why variant classification is distinct from assessing whether variants are explanatory in a clinical context. And please allow me to introduce a neologism: explanatoriness. Continue reading

Must love rules: an insider’s guide to variant sciences

Unknown significance. Quite possibly the two most dreaded words in clinical genetics. To some these two words should seldom be used let alone act as qualifiers for testing results. What are the rules of assessment? How do laboratories determine what constitutes enough evidence to say that a variant, previously known as mutation, is of known significance?   Continue reading