(The American Journal of Human Genetics 94, 649–661; May 1, 2014) In this article, the authors reported on four individuals with intellectual disability, severely affected speech development, behavioral problems, and missense mutations affecting the SAND domain of DEAF1. Functional studies showing a loss of function of DEAF1 and behavioral studies in a conditional knockout mouse provided additional support for causality of the DEAF1 mutations in these four reported individuals. Late in the review process, an additional SCN2A mutation (c.1570C > T [p.Arg524∗]) leading to a truncating allele was identified in one of the four subjects (individual 3) and was added to Table 1. Mutations in SCN2A have been associated with benign familial infantile seizures (BFIC3 [MIM 607745]), autism spectrum disorder (ASD), and early infantile epileptic encephalopathy 11 (E1EE11 [MIM 613721]). Whereas missense mutations in SCN2A have been associated with both BFIC3 and E1EE11, truncating mutations have so far only been observed among individuals with ASD and E1EE11. In a recent review by Baasch et al., 33 different SCN2A mutations in 14 families affected by benign forms of epilepsy and in 21 subjects with severe phenotypes were reported.1 Whereas the mutations leading to a milder phenotype were almost all inherited, the majority of mutations (either missense or truncating) associated with a severe phenotype occurred de novo.1 In addition, using a statistical approach, Samocha et al. recently showed that SCN2A is one of the genes that is significantly enriched with de novo mutations in ASD subjects and in individuals with intellectual disability, whereas Feenstra et al. found an association with febrile seizures in general via a genome-wide association study.2,3 Therefore, it is reasonable to assume that the SCN2A mutation in individual 3 in the present article influenced the severity of the intellectual disability in this 10-year-old boy. However, the authors observed that his clinical presentation was similar to that of the other three presented persons with a missense mutation affecting the SAND1 domain of DEAF1 and that he did not have a history of epilepsy. The authors want to stress that because of the rapid development of techniques, increasing numbers of potential pathogenic mutations in multiple genes will be detected in each individual, and currently an average of 1.58 de novo mutations in the exome are already found per person with intellectual disabilty.4 This not only requires caution in the interpretation of a recurrent single gene defect but also requires additional clinical and functional support for ascertaining its pathogenicity.
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