Fig. 1: Frequency, size, interpretation, and distribution of copy-number variants (CNVs) observed in clinically tested genes.

a Histogram showing the number of distinct CNVs observed in the tested genes. The columns in the chart indicate the number of times the CNVs were observed. The line graph shows the proportion of total observed CNVs in each frequency bin. For example, the first column shows that nearly 900 CNVs occurred just once and, in aggregate, accounted for roughly 30% of all CNVs. b Histogram showing the number of genes that contained CNVs in our clinical cohort. The columns in the chart show incremental increases in the number of CNVs observed in a gene. The line graph shows the proportion of CNVs at arbitrary increments of CNV occurrence per gene. For example, nearly 200 genes had just 1 CNV, which together accounted for less than 10% of all events. By contrast, approximately 30 genes had more than 15 CNVs each, which represented nearly 70% of all CNVs. c Distribution of deletions and duplications by number of exons affected and by clinical interpretation. Cytogenetic events are defined as contiguous CNVs of the same zygosity affecting neighboring genes on a single chromosome. Some whole-gene events may in fact be part of larger cytogenetic events but are not listed as such because other genes within the predicted cytogenetic event were absent from our assay and therefore unavailable for analysis. d Count of CNV duplications and deletions detected in clinical and baseline CNV data. CNVs are split into those including a whole gene (classes I, V), at least the last exon (classes II, VI), at least the first exon (classes III, VII), or only an internal exon(s) (classes IV, VIII). A generic gene structure is shown at the top. Green and purple boxes denote “terminal exons” and all others are “internal exons,” as described in the text. Empty boxes indicate deleted exons. This figure assumes that intragenic duplications occur in tandem, which is often the case with such events. CNVs involving just promoter regions are not represented in this figure. A Pearson’s chi-squared contingency table gives a p value of p < 1×10⁻⁵ for duplications and p = 1.5×10⁻⁵ for deletions, indicating that the difference in the distribution of CNVs across the gene is not merely due to sampling differences between clinical and baseline CNVs. e and f Deletions and duplications in clinically tested genes and their interpretations. The chart in (e) shows genes with loss-of-function (LOF) mutational mechanisms, and that in (f) shows genes without loss-of-function (LOF) mechanisms. Most genes included in our panels were curated as having LOF mechanisms. The clinical classification of each CNV, inheritance pattern of the gene with the CNV, and zygosity of the variants are compared. For X-linked (XL) genes, heterozygous CNVs in females are shown separately from CNVs in males. AD autosomal dominant, AR autosomal recessive, F female, het heterozygous, hom homozygous, M male, LP likely pathogenic variant, P pathogenic variant, VUS variants of uncertain significance. The “Pathogenic” label in c, e, and f includes CNVs classified as pathogenic and likely pathogenic