Tychele N Turner, Kamal Sharma, Edwin C Oh, Yangfan P Liu, Ryan L Collins, Maria X Sosa, Dallas R Auer, Harrison Brand, Stephan J Sanders, Daniel Moreno-De-Luca, Vasyl Pihur, Teri Plona, Kristen Pike, Daniel R Soppet, Michael W Smith, Sau Wai Cheung, Christa Lese Martin, Matthew W State, Michael E Talkowski, Edwin Cook, Richard Huganir, Nicholas Katsanis, Aravinda Chakravarti
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos...
April 2, 2015: Nature