Fig. 4

Burden of other hits modulates quantitative phenotypes among probands with a first-hit copy-number variant (CNV) or single-nucleotide variant (SNV) associated with neurodevelopmental disease. (a) Negative correlation between the number of other hits and full-scale IQ (FSIQ) scores in individuals (n = 53) carrying 16 CNVs associated with neurodevelopmental disease (Pearson correlation, R = –0.36, p = 0.004). Probands with 16p11.2 deletion (red), 16p11.2 duplication (green), 1q21.1 duplication (blue) and 7q11.23 duplication (yellow) are highlighted, while gray circles represent probands with other rare CNVs. (b) Higher burden of other hits among probands with 16p11.2 deletion and FSIQ <70 (n = 17) compared with probands with FSIQ ≥70 (n = 65, one-tailed Mann–Whitney, p = 0.08). (c) Negative correlation between the number of other hits and head circumference z-scores (age ≥12 months, n = 80, Pearson correlation R = –0.26, p = 0.009) in probands with 16p11.2 deletion. (d) Autism probands with de novo disruptive variants and available FSIQ scores (n = 290) show a moderate negative correlation (Spearman correlation coefficient, R = –0.25, p < 0.0001) between the number of other hits and FSIQ scores. (e) Probands present an excess of other hits compared with their unaffected siblings (n = 184 pairs) carrying the same inherited pathogenic variants (loss-of-function or damaging missense CADD ≥25) in genes recurrently disrupted in neurodevelopmental disease (Wilcoxon signed-rank test, p = 0.03). (f) Enrichment of other hits among individuals with damaging variants in SCN1A (loss-of-function or missense CADD ≥25) and intellectual disability (one-tailed Mann–Whitney, p = 0.02) compared with those without intellectual disability