DNM1 and when transcripts matter more than genes

What comes next. Earlier this month, Ingo made a bit of a splash at the American Epilepsy Society Annual Course, with his surprising comment that, in some contexts, “genes don’t matter.” This was in reference to transcripts and gene expression, which ultimately determine if and how variants can cause disease. In this post, I wanted to explore this idea, diving into the world of transcripts and their increasing relevance in approaching diagnosis and treatment of genetic epilepsies and neurodevelopmental disorders. And I wanted to share one of the most surprising findings in epilepsy genetics in 2022, namely, how examining transcripts rather than genes helped us understand how an intronic variant can be dominant-negative. Continue reading

Critical brain-expressed exons and de novo mutations in autism

Selection. De novo mutations in neurodevelopmental disorders including autism, schizophrenia, and intellectual disability raise an important question: are the mutations identified in patients pathogenic or are they simply genomic noise? A recent study in Nature Genetics tries to answer this question by looking at expression of particular exons in the brain and the overall mutational burden in these exons. They come up with critical exons, which seem to be particularly vulnerable in Autism Spectrum Disorder. Continue reading

DUF1220, autism, and highly dosage-variable genes

Copy numbers. When we discuss structural genomic variants in the human genome on the Channelopathist blog, we usually refer to regions where simple deletions or duplications exert a pathogenic effect. However, there are also genes that are highly copy number variable, sometimes present at 80 copies or more. Copy numbers of a few of these genes have expanded during human evolution recently, turning these genes into potential candidate genes for human disease. A recent paper in PLOS Genetics now examines the role of DUF1220, which encodes a protein domain of the NBPF genes. This domain shows an unusually broad range of copy number variation in the human genome. Interestingly, this gene resides right next to the 1q21.1 region that is implicated in various neurodevelopmental disorders. Continue reading