Fig 1.
a) Technical bias across the genome remains after stringent correction and filtering. The distribution of the bin inter-sample mean coverage in the epilepsy cohort (red) is compared to null distributions (blue: bins shuffled, green: simulated normal distribution). b) PopSV approach. First the genome is fragmented and reads mapping in each bin are counted for each sample and GC corrected (1). Next, coverage of the sample is normalized (2) and each bin is tested by computing a Z-score (3), estimating p-values (4) and identifying abnormal regions (5). c) Number and proportion of calls from a twin that was replicated in the other monozygotic twin.
Fig 2.
CNVs in the epilepsy and control cohorts.
a) Regions with a CNV in each epilepsy patient. b) Each CNV in the CNV catalog of the epilepsy and control cohorts was annotated with its maximum frequency in five CNV databases. c) Enrichment in exonic sequence for all CNVs (left) and rare CNVs (right), larger than 50 Kbp (top) or smaller than 50 Kbp (bottom). The fold-enrichment (y-axis) represents how many CNVs overlap coding sequences compared to control regions randomly distributed in the genome.
Table 1.
Real-Time PCR validation rates of PopSV calls.
Fig 3.
a) Number of rare CNVs in or close to exons of protein-coding genes (top) or epilepsy genes (bottom), in the epilepsy cohort. b) Number of epilepsy genes hit by exonic deletions in the epilepsy cohort and never seen in the public and internal databases (dotted line), compared to the expected distribution in all genes and size-matched genes (histograms). c) Rare non-coding CNVs in functional regions near epilepsy genes. The graph shows the cumulative number of individuals (y-axis) with a rare non-coding CNV located at X Kbp or less (x-axis) from the exonic sequence of a known epilepsy gene. We used CNVs overlapping regions functionally associated with the epilepsy gene (eQTL or promoter-associated DNase site).
Fig 4.
Exonic CNVs in CHD2 detected by PopSV.
The ‘CNV’ panel shows the exonic deletions (blue) and duplications (red) called by PopSV. The ‘Coverage’ panel shows the read depth signal in the affected individuals (colored points/lines) and the coverage distribution in the reference samples (boxplot and grey point).
Table 2.
Pathogenic profiles in known epilepsy genes.
Table 3.
Recurrent CNVs with a pathogenic profile.