Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Maria Delio, Tingwei Guo, Donna M. McDonald-McGinn, Elaine Zackai, Sean Herman, Mark Kaminetzky, Anne Marie Higgins, Karlene Coleman, Carolyn Chow, Maria Jarlbrzkowski, Carrie E. Bearden, Alice Bailey, Anders Vangkilde, Line Olsen, Charlotte Olesen, Flemming Skovby, Thomas M. Werge, Ludivine Templin, Tiffany Busa, Nicole Philip, Ann Swillen, Joris R. Vermeesch, Koen Devriendt, Maude Schneider, Sophie Dahoun, Stephan Eliez, Kelly Schoch, Stephen R. Hooper, Vandana Shashi, Joy Samanich, Robert Marion, Therese van Amelsvoort, Erik Boot, Petra Klaassen, Sasja N. Duijff, Jacob Vorstman, Tracy Yuen, Candice Silversides, Eva Chow, Anne Bassett, Amos Frisch, Abraham Weizman, Doron Gothelf, Maria Niarchou, Marianne van den Bree, Michael J. Owen, Damian Heine Suñer, Jordi Rosell Andreo, Marco Armando, Stefano Vicari, Maria Cristina Digilio, Adam Auton, Wendy R. Kates, Tao Wang, Robert J. Shprintzen, Beverly S. Emanuel, Bernice E. Morrow

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6-1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin.