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

16p13.11 microdeletions and the male bias

The enigmatic deletion. Amongst the various microdeletions implicated in human epilepsy, the 16q13.11 microdeletion is one of the structural variations that poses significant difficulties in understanding its associated risk and phenotypes. Now a recent paper in PLOS One investigates a large cohort of patients with various neurodevelopmental disorders for microdeletions in the 16p13.11 region. And particularly the finding regarding the sex distribution of symptomatic deletion carriers is remarkable.   Continue reading

“Meta-channelopathies” – RBFOX1 deletions and human epilepsy

Man is built to seize. When Hughlings Jackson made this famous comment pertaining to the inherent hyperexcitability of the human brain in response to a wide range of different stimuli, he probably didn’t anticipate the mechanisms of splicing regulation. Our CNS is actively protected from hyperexcitability through directed splicing of ion channel mRNA. Now, a recent study in Epilepsia finds that these mechanisms may be dysfunctional in human epilepsy. Continue reading

AUTS2, regulatory elements and human evolution

Recurrent themes. The era of large-scale genomics in neurodevelopmental disorders has welcomed the discovery of several genes, which predispose to a wide range of neurodevelopmental disorders. While a connection to neuronal function is obvious for a few of them, the function of other genes remains cryptic. Now, a recent paper in PLOS Genetics investigates AUTS2, a gene that is both a candidate gene for autism and a gene that has changed dramatically in recent human evolution. Continue reading