Our results illustrate both the challenges and the potential of whole exome sequencing in an extremely genetically heterogeneous condition such as autism. Each exome contains large numbers of variants that initially challenge analysis. We present a systematic method to approach whole exome data, by filtering for variants compatible with identity by descent, surveying prevalence in controls, segregation analysis, and incorporating functional information (Figure 2). Almost all instances in which new genetic syndromes have been identified using whole exome or whole genome sequencing have involved families with recessive disorders generally (Miller syndrome) [37], [38] and/or shared parental ancestry specifically (WDR62-associated cortical malformations) [39], because the analysis of homozygous mutations provides tremendous power to improve “signal to noise” caused by sequencing errors, spontaneous cell line mutations, somatic mutations, etc. Hence, tracing ancestry may be an important tool to define genetic causes in a subset of autism patients. Our study further emphasizes the power of whole exome and whole genome approaches in allowing a complete survey of all potential mutations in the patient genome, and the systematic screening of all major modes of
