Risk of meningomyelocele mediated by the common 22q11.2 deletion.
Keng Ioi VongSangmoon LeeKit Sing AuTerrence Blaine CrowleyValeria CapraJeremiah MartinoMeade HallerCamila AraújoHélio R MachadoRenee GeorgeBryn GerdingKiely N JamesValentina StanleyNan JiangKameron AluNaomi MeaveAnna S NidhiryFiza JiwaniIsaac TangAshna NisalIshani JhambArzoo PatelAakash PatelJennifer McEvoy-VenneriChelsea BarrowsCelina ShenYoo-Jin HaRobyn HowarthMadison StrainAllison Elizabeth Ashley-KochMatloob AzamSara MumtazGyang Markus BotRichard H FinnellZoha KibarAhmed I MarwanGia MelikishviliHal S MeltzerOsvaldo M MutchinickDavid A StevensonHenry J MroczkowskiBetsy OstranderErica SchindewolfJulie MoldenhauerElaine H ZackaiBeverly S EmanuelSixto García-MiñaúrSebastian KwiatkowskiRoger E StevensonMaha Saad ZakiHope NorthrupHanna K McNamaraKimberly A AldingerIan G PhelpsMei DengIan A Glassnull nullBernice E MorrowDonna M McDonald-McGinnSimone Sanna-CherchiDolores J LambJoseph G GleesonPublished in: Science (New York, N.Y.) (2024)
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.