Risk of meningomyelocele mediated by the common 22q11.2 deletion
Keng Ioi Vong, Sangmoon Lee, Kit Sing Au, T. Blaine Crowley, Valeria Capra, Jeremiah Martino, Meade Haller, Camila Araújo, Hélio Rubens Machado, Renee D. George, Bryn Gerding, Kiely N. James, Valentina Stanley, Nan Jiang, Kameron Alu, Naomi Meave, Anna S. Nidhiry, Fiza Jiwani, Isaac Tang, Ashna Nisal, Ishani Jhamb, Arzoo Patel, Ishani Jhamb, Jennifer McEvoy‐Venneri, Chelsea Barrows, Celina Shen, Yoo-Jin Ha, Robyn E. Howarth, Madison Strain, Allison E. Ashley‐Koch, Matloob Azam, Sara Mumtaz, Gyang Markus Bot, Richard H. Finnell, Zoha Kibar, Ahmed I. Marwan, Gia Melikishvili, Hal S. Meltzer, Osvaldo M. Mutchinick, David A. Stevenson, Henry J. Mroczkowski, Betsy Ostrander, Erica Schindewolf, Julie S. Moldenhauer, Elaine H. Zackai, Beverly S. Emanuel, Sixto García‐Miñáur, Beata Nowakowska, Roger E. Stevenson, Maha S. Zaki, Hope Northrup, Hanna K. McNamara, Kimberly A. Aldinger, Ian G. Phelps, Mei Deng, Ian A. Glass, Bernice E. Morrow, Donna M. McDonald‐McGinn, Simone Sanna‐Cherchi, Dolores J. Lamb, Joseph G. Gleeson, Allison E. Ashley‐Koch, Hal S. Meltzer, Joan T. Le, Kit Sing Au, Hope Northrup, Gyang Markus Bot, Valeria Capra, Richard H. Finnell, Zoha Kibar, Philip J. Lupo, Hélio Rubens Machado, Camila Araújo, Helio R. Machado, Ahmed I. Marwan, Gia Melikishvili, Osvaldo M. Mutchinick, Roger E. Stevenson, Anna Yurrita, Maha S. Zaki, Sara Mumtaz, José Ramón Medina-Bereciartu, Caroline M. Kolvenbach, Shirlee Shril, Friedhelm Hildebrandt, Mahmoud M. Noureldeen, Aida M. S. Salem, Yukitoshi Takahashi, Hormos Salimi-Dafsari, H. Westley Phillips, Brian W. Hanak, Bülent Kara, Ayfer Sakarya Güneş, David Gonda, Salman Kirmani, Tinatin Tkemaladze, Joseph G. Gleeson, Tinatin Tkemaladze, Joseph G. Gleeson
Abstract
Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl , one of several neural tube–expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.