Genome-wide CNV and SNV data were overlaid using custom algorithm and IVA in order to detect genomic loci harboring multiple types of deleterious variants in 13 probands.
Consistent with several studies suggesting digenic inheritance of HL, the concept of a mutational load, whereby an excess of deleterious variants scattered across multiple genes impedes the proper functioning of auditory processes, is an interesting perspective on a typically Mendelian disorder.
The difference in convulsive seizure frequency between the SUDEP and epilepsy control groups is also not significant after correction for multiple comparisons, but it is interesting to speculate whether genome-wide burden of deleterious variants is an explanation that might underlie this epidemiologically-derived risk factor, tying epilepsy severity into genomic burden.
Currently, the user may supply candidate disease genes in the following formats: a single or multiple genomic region(s), specified by chromosome and interval boundaries; a pre-filtered VCF file containing potentially deleterious variants (enforced by file size limit); a candidate gene list in a delimited format, accepting several commonly used delimiter types.
By including information from multiple data sources ranging from the widely agreed upon and adjudicated variants in ClinVar [ 10] to predicted deleterious variants using dbNSFP [ 11], we were able to establish the lower and upper bounds, respectively, of both the SFs and recessive carrier alleles in diverse populations.
Signing variants greatly improved the efficiency when both protective and deleterious variants are present, although some efficiency was lost when only deleterious alleles were present.
Purifying selection at some locus can inflate the contrast observed between loci with some having registered well the period of allopatry with multiple fixations (e.g. CO1, SAHH, LYSO) while other loci having evolved too slowly and exhibiting an excess of rare, slightly deleterious, variants (e.g. EF1α, ITS2; see Figure 11).
Disruption of BDNF-regulated YY1 transcription could therefore exert multiple deleterious neural effects.
After excluding non-deleterious variants, we observed 32,213 unique deleterious variants occurring 105,323 times.
