Distinct gene-set burden patterns underlie common generalized and focal epilepsies

in EBioMedicine (2021), 72

Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of ... [more ▼]

Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. Methods The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. Findings Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. Interpretation Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. [less ▲]

Predicting functional effects of missense variants in voltage-gated sodium and calcium channels

in Science Translational Medicine (2020), 12(556), 6848

Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases ... [more ▼]

Malfunctions of voltage-gated sodium and calcium channels (encoded by SCNxA and CACNA1x family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF (n = 518) and GOF (n = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCNxA/CACNA1x family genes. [less ▲]