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We agree with Shohat and Shifman that the proportion of ASD genes that are long may drop as more ASD genes are identified. We did not account for how the discovery method used to identify a given ASD candidate, be it based on copy number variant (CNV) or single nucleotide variant (SNV), might affect average gene length in our study. However, it is also undeniable that many long genes are considered candidates in ASD pathology, such as NRXN1 and CNTNAP2. Moreover, our mechanistic findings are not in dispute. Indeed, three other groups came to the same conclusion as us—that topoisomerases preferentially facilitate expression of long genes3,4,5. Our study demonstrates an essential role for topoisomerases in transcriptional elongation of long neuronal genes and suggests a critical role for these enzymes in neurodevelopmental disorders like autism.

Shohat and Shifman1 also suggest that the SFARI Gene database contains many genes with weak links to ASD pathology. In our study, we did not rank genes as stronger or weaker ASD candidates, and treated all equally. However, when the degree of evidence behind each candidate is taken into account, using the gene scoring module in SFARI Gene 2.06 (as of 1 April 2014), it remains clear that numerous strong ASD candidate genes are very long (>200 kilobases). Thus, we feel our conclusion linking topoisomerases and gene length with autism is still warranted, but this remains to be tested more rigorously pending in vivo studies with animal models and additional human genetic studies.

Future studies are likely to validate additional long genes as strong ASD candidates. For example, NRXN3 and CNTN5 (1.5 and 1.3 megabase, respectively) are not yet scored in SFARI Gene, yet these genes are deleted in patients with ASD7,8 and both are significantly reduced in topotecan-treated neurons2.

Ultimately, we agree that making conclusions about the nature of ASD genes is complicated by factors like the ones Shohat and Shifman describe1 as well as by the evolving knowledge of autism genetics. Regardless, we identified a transcriptional mechanism that affects the expression of long genes, a number of which are currently classified as strong ASD candidates.