Supp. Table S5. Paralogous Annotation applied reciprocally to nine epilepsy genes that are homologous to LQT genes.

To demonstrate the wider applicability of paralogous annotation beyond LQT genes we have used the same method to annotate epilepsy genes. Many of the paralogues of LQT genes identified in this study cause neurological disease that may be attributable to changes in membrane stability due to ion channel dysfunction. For example, we noted that paralogues of LQT genes account for more than half of epilepsy-related variants reported in HGMD. For 9 epilepsy genes listed below we used sites of known disease-causing variation in paralogues, including LQT genes, to identify variants that we predict would be intolerant of variation in epilepsy genes, using the same multiple-sequence alignments previously described. Where paralogue annotation identifies a residue associated with a known phenotype we see an enrichment of disease-causing residues, as for LQT syndrome (p=0.0033, Fisher's exact, two-tailed).

For each gene, the protein residue number and reference allele are shown, followed by details of known variation at that residue. Known variants are classified as “Epilepsy” (reported to cause to an inherited seizure syndrome), “Other Disease Phenotype” (reported either as a "possible" cause of inherited seizures, or as a cause of another neurological phenotype, such as migraine or a pain syndrome), “Benign”, “Probably Benign”, or “Conflict” (where sources disagree). “None” indicates that no variants have been reported at this position. Pubmed identifiers are given in brackets for primary references, together with dbSNP identifiers where available.

Where a disease-causing variant in a paralogue maps to an epilepsy protein residue, the paralogue gene and transcript ID are given, followed by details of the disease, variant and Pubmed identifiers for primary references. The consensus score (0-9) indicates the strength of agreement of different multiple-sequence alignment algorithms at that residue – a high score suggests confidence in the alignment at that position. Alignments (generated using M-Coffee) are available as supplementary files, accessible via the hyperlinks below.