Fig. 2

Rare variants in the genetic background contribute to the phenotypic heterogeneity in 16p12.1 deletion. (a) Phenotypic spectrum of 16p12.1 deletion in probands (n=141, red) and carrier parents (n=39, gray). Probands exhibit a spectrum of severe developmental features compared with the mild cognitive and psychiatric features observed in carrier parents. Features represented were observed in ≥5% of probands or carrier parents. (b) Example of families with inherited 16p12.1 deletion. Family 1 (left) shows three generations carrying 16p12.1 deletion and multiple neurodevelopmental and psychiatric features, with the proband (P1C_01, indicated with arrow) carrying a de novo loss-of-function variant in SETD5 (p.Asp542Thrfs*3) and a stopgain variant in DMD gene (p.Trp3X) inherited from the mother without the 16p12.1 deletion (noncarrier). Family 2 (right) shows a proband (PC_11, indicated with arrow) with multiple congenital and neurodevelopmental features carrying 16p12.1 deletion and 2p16.3 deletion (encompassing NRXN1), the latter inherited from the noncarrier mother. (c) Analysis of rare (≤0.1%) likely deleterious variants (single-nucleotide variants with CADD ≥25) in genes intolerant to functional variation (RVIS ≤20th percentile) in proband–carrier parent pairs shows that probands present a higher burden of other hits compared with their carrier parents (n=23, Wilcoxon signed-rank test, p=0.004). ADHD attention deficit hyperactivity disorder