Risk of meningomyelocele mediated by the common 22q11.2 deletion

• 成果类型: Article
• 署名作者: Vong, Keng Ioi; Lee, Sangmoon; Au, Kit Sing; Crowley, T. Blaine; Capra, Valeria; Martino, Jeremiah; Haller, Meade; Araujo, Camila; Machado, Helio R.; George, Renee; Gerding, Bryn; James, Kiely N.; Stanley, Valentina; Jiang, Nan; Alu, Kameron; Meave, Naomi; Nidhiry, Anna S.; Jiwani, Fiza; Tang, Isaac; Nisal, Ashna; Jhamb, Ishani; Patel, Arzoo; Patel, Aakash; McEvoy-Venneri, Jennifer; Barrows, Chelsea; Shen, Celina; Ha, Yoo-Jin; Howarth, Robyn; Strain, Madison; Ashley-Koch, Allison Elizabeth; Azam, Matloob; Mumtaz, Sara; Bot, Gyang Markus; Finnell, Richard H.; Kibar, Zoha; Marwan, Ahmed I.; Melikishvili, Gia; Meltzer, Hal S.; Mutchinick, Osvaldo M.; Stevenson, David A.; Mroczkowski, Henry J.; Ostrander, Betsy; Schindewolf, Erica; Moldenhauer, Julie; Zackai, Elaine H.; Emanuel, Beverly S.; Garcia-Minaur, Sixto; Nowakowska, Beata A.; Stevenson, Roger E.; Zaki, Maha S.; Northrup, Hope; McNamara, Hanna K.; Aldinger, Kimberly A.; Phelps, Ian G.; Deng, Mei; Glass, Ian A.; Koch, Allison Elizabeth Ashley; Le, Joan; Lupo, Philip J.; Magana, Tony; Marwan, Ahmed, I; Yurrita, Anna; Zaki, Maha S.; Medina-Bereciartu, Jose Ramon; Kolvenbach, Caroline M.; Shril, Shirlee; Hildebrandt, Friedhelm; Noureldeen, Mahmoud M.; Salem, Aida MS.; Takahashi, Yukitoshi; Salimi-Dafsari, Hormos; Phillips, H. Westley; Hanak, Brian; Kara, Bulent; Gunes, Ayfer Sakarya; Gonda, David D.; Kirmani, Salman; Tkemaladze, Tinatin; Morrow, Bernice; McDonald-McGinn, Donna M.; Sanna-Cherchi, Simone; Lamb, Dolores J.; Gleeson, Joseph G.
• 署名单位: University of California System; University of California San Diego; University of Texas System; University of Texas Health Science Center Houston; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Genoa; IRCCS Istituto Giannina Gaslini; Columbia University; Baylor College of Medicine; Baylor College of Medicine; Universidade de Sao Paulo; Duke University; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Universite de Montreal; University of Colorado System; University of Colorado Anschutz Medical Campus; Children's Hospital Colorado; Rady Childrens Hospital San Diego; University of California System; University of California San Diego; Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran - Mexico; Stanford University; University of Tennessee System; University of Tennessee Health Science Center; Utah System of Higher Education; University of Utah; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Hospital Universitario La Paz; Greenwood Genetic Center; Egyptian Knowledge Bank (EKB); National Research Centre (NRC); Seattle Children's Hospital; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Sapienza University Rome; Cornell University; Weill Cornell Medicine; Duke University; West Virginia University; Rady Childrens Hospital San Diego; University of Texas System; University of Texas Health Science Center Houston; University of Genoa; IRCCS Istituto Giannina Gaslini; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Universite de Montreal; Baylor College of Medicine; Universidade de Sao Paulo; Mekelle University; University of Missouri System; University of Missouri Columbia; Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran - Mexico; Greenwood Genetic Center; Egyptian Knowledge Bank (EKB); National Research Centre (NRC); Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Egyptian Knowledge Bank (EKB); Beni Suef University; University of Cologne; Stanford University; Childrens Hospital of Orange County; Kocaeli University; Aga Khan University; Tbilisi State Medical University; University of California System; University of California San Diego
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12235
• DOI: 10.1126/science.adl1624
• 发表日期: 2024-05-03
• 页码: 584-590
• 关键词: neural-tube defects; mutations; proliferation; snap29; folate; crkl

摘要

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.