For ASD there is a notably strong prima facie case for there being a a cardinal role for rare variation. Karyotyping studies suggested that on the order of 5% of ASD cases have one of a large number of rare but relatively gross chromosomal abnormalities. 14,78 In addition, ASD has been noted as a comorbid feature of >100 single gene, Mendelian medical genetic syndromes, 79 although the penetrance and confidence of the clinical associations are variable. Indeed, ASD mutations with very high penetrance are exceptional (i.e., Rett syndrome mutations in MECP2 and CDKL5), and Mendelian diseases enriched for ASD have far less than complete penetrance (e.g., Fragile X syndrome and tuberous sclerosis). 78
