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XB-ART-61317
Nature 2025 Mar 26; doi: 10.1038/s41586-025-08676-x.
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The contribution of de novo coding mutations to meningomyelocele.

Ha YJ , Nisal A , Tang I , Lee C , Jhamb I , Wallace C , Howarth R , Schroeder S , Vong KI , Meave N , Jiwani F , Barrows C , Lee S , Jiang N , Patel A , Bagga K , Banka N , Friedman L , Blanco FA , Yu S , Rhee S , Jeong HS , Plutzer I , Major MB , Benoit B , Poüs C , Heffner C , Kibar Z , Bot GM , Northrup H , Au KS , Strain M , Ashley-Koch AE , Finnell RH , Le JT , Meltzer HS , Araujo C , Machado HR , Stevenson RE , Yurrita A , Mumtaz S , Ahmed A , Khara MH , Mutchinick OM , Medina-Bereciartu JR , Hildebrandt F , Melikishvili G , Marwan AI , Capra V , Noureldeen MM , Salem AMS , Issa MY , Zaki MS , Xu L , Lee JE , Shin D , Alkelai A , Shuldiner AR , Kingsmore SF , Murray SA , Gee HY , Miller WT , Tolias KF , Wallingford JB , Spina Bifida Sequencing Consortium , Kim S , Gleeson JG .


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Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.

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Species referenced: Xenopus laevis
Genes referenced: adgrb3 adgrv1 adra2b ash1l aspm atxn7 bicra brat1 brsk2 bsg capn3 celsr1 clip2 cltc cntnap1 cul3 cyb561 dag1 dcx dhcr7 dnah11 dnah5 dpysl2 ep300 fem1c frem1 gmppb grhl2 grhl3 gria3 hectd4 inf2 irs1 itpr3 kdm1a kdm5b kif22 lama3 lemd3 loxhd1 map2 med13l mink1 mmut mthfr mybpc3 myo6 nckap1l nostrin pax3 pck2 pex3 pla2g7 plce1 plg pogz pop1 prepl scaper scrib sdhaf1 sec31a shroom3 slc4a4 slco1b3 spen sqor tbxas1 tbxt tcf12 tiam1 timm50 tnk2 top2b ubiad1 unc80 vangl1 vangl2 vps13c vps50 vwa8 whamm zswim6
GO keywords: Wnt signaling pathway

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