Vong Keng Ioi, Lee Sangmoon, Au Kit Sing, Crowley T Blaine, Capra Valeria, Martino Jeremiah, Haller Meade, Araújo Camila, Machado Hélio 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, Morrow Bernice, McDonald-McGinn Donna M, Sanna-Cherchi Simone, Lamb Dolores J, Gleeson Joseph G
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA.
Science. 2024 May 3;384(6695):584-590. doi: 10.1126/science.adl1624. Epub 2024 May 2.
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 , 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.
脊髓脊膜膨出是神经管缺陷（NTDs）最严重的形式之一，也是中枢神经系统最常见的结构出生缺陷。我们组建了脊柱裂测序联盟来确定病因。对715个亲子三联体进行外显子组和基因组测序，发现6名患者存在22q11.2染色体缺失，提示与普通人群相比风险增加了23倍。此外，对一个单独的22q11.2缺失队列的分析表明，脊髓脊膜膨出的NTD风险增加了12至15倍。最小缺失区间内几个神经管表达基因之一的缺失，足以在小鼠中复制NTDs，在小鼠中，母体叶酸缺乏会加剧外显率和表现度。因此，常见的22q11.2缺失会带来显著的脊髓脊膜膨出风险，补充叶酸可部分缓解这种风险。
