Having established that de novo damaging variants occur more frequently in OCD probands, we next asked whether these variants cluster within specific genes. We identified three genes with multiple (≥2) de novo LGD or Mis-D variants in unrelated probands. Using TADA (40) and previously established false discovery rate (FDR) thresholds, two of these genes met criteria for high-confidence risk genes (q<0.1): SCUBE1 (Signal Peptide, CUB Domain And EGF Like Domain Containing 1; q=0.091) and CHD8 (Chromodomain Helicase DNA Binding Protein 8; q=0.098). A third gene, TTN (Titin), did not meet this threshold (q=0.63) (Table 2, Table S5). For SCUBE1 and CHD8, we observed one de novo Mis-D variant and one de novo canonical splice site variant each. Each of the splice site variants decrease splicing efficiency as predicted by MaxEntScan scores (44) (88% decrease from 9.94 to 1.19 for CHD8; 100% decrease from 7.75 to −0.44 for SCUBE1) (Ingenuity Variant Analysis, Qiagen Bioinformatics).
