Improving diagnostic yield in rare diseases through phenotypic-driven approaches

NDD. Family-based (trio) exome sequencing has become the standardized method for identifying genetic etiologies that cause neurodevelopmental disorders. De novo variants have been responsible for the majority of pathogenic genetic findings, although the landscape of genetic disorders overall is highly heterogeneous. In a recently published study, the authors assessed variant classification to identify new molecular diagnoses and factors influencing the likelihood of receiving a diagnosis. The study reported a diagnostic yield of over 41%, highlighting 60 new genes associated with developmental disorders. The authors also emphasized the importance of structured and detailed phenotypic information for improving variant interpretation. This blog post provides a brief review of their publication in the context of improving diagnostic yield using a phenotypically driven approach in rare diseases.

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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

The Zero ExAC problem

Evidence and absence. There is a time before and after ExAC, the gigantic variant repository based on more than 60,000 exomes sequenced at the Broad Institute. ExAC was released in October 2014 and has suddenly provided the community with access to variant data of roughly ten times more individuals than previous resources. But what happens when you check variants that were previously considered pathogenic and they are seen at low frequency in ExAC? Welcome to the Zero ExAC problem, providing us with a taste of the complications that epilepsy gene variant interpretation will face in the future. Continue reading