Whole-blood DNA was enriched for exonic sequences (exome capture) through hybridization with a NimbleGen custom array (n=210) or EZExomeV2.0 (n=718). The captured DNA was sequenced using an Illumina GAIIx (n=592) or HiSeq 2000 (n=336). Short read sequences were aligned to hg18 with BWA,6 duplicate reads were removed and variants were predicted using SAMtools.7 The data was normalized across each family by only analyzing bases with at least 20 unique reads in all family members (Supplementary Information). De novo predictions were made blinded to affected status using experimentally verifed thresholds (Supplementary Information). All de novo variants were confirmed using Sanger sequencing blinded to affected status.
