No Evidence for Association of Autism with Rare Heterozygous Point Mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins

John D. Murdoch, Abha R. Gupta, Stephan J. Sanders, Michael F. Walker, John Keaney, Thomas V. Fernandez, Michael T. Murtha, Samuel Anyanwu, Gordon T. Ober, Melanie J. Raubeson, Nicholas M. DiLullo, Natalie Villa, Zainabdul Waqar, Catherine Sullivan, Luis Gonzalez, A. Jeremy Willsey, So-Yeon Choe, Benjamin M. Neale, Mark J. Daly, Matthew W. State

Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.