From the Rady Children's Institute for Genomic Medicine, San Diego (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., J.G.G.), and the University of California, San Diego, La Jolla (G.C., C.C., Z.L., L.W., T.M., N.J., X.Y., J.M.-V., V.S., P.A., N.L., K.W., J.G.G.) - both in California; Xuanwu Hospital, Capital Medical University, Beijing (G.C.); the Genome Institute of Singapore (E.S.-R., M.K., V.W., B.R.) and the Institute of Molecular and Cellular Biology (B.R.), Agency for Science, Technology, and Research, and the Program in Cancer and Stem Cell Biology, Duke-NUS (National University of Singapore) Medical School (J.Y., D.M.V.) - all in Singapore; the Medical Genetics Department, Koç University School of Medicine, Istanbul, Turkey (B.R.); the Department of Pediatrics, Duke University, Durham, NC (D.M.V.); the Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center (R.N., F.M.), and the Departments of Pediatrics and Medicine, Columbia University (R.H., W.K.C.) - both in New York; Centogene, Rostock, Germany (R.M., A.M.B.-A.); DNA Laboratório e Genética Médica, Salvador, Brazil (M.B.P.T., P.M.L.P.); the Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India (R.D.P.); Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia (N.A.-S.); and the Clinical Genetics Department, National Research Center, Cairo (M.S.Z.).
N Engl J Med. 2021 Sep 30;385(14):1292-1301. doi: 10.1056/NEJMoa2033911.
Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach.
We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring.
We identified homozygous mutations in , which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development.
Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).
结构出生缺陷约占活产儿的 3%；大多数此类缺陷缺乏明确的遗传或环境原因。尽管手术方法有所进步，但药物预防在很大程度上仍难以实现。
我们在包括神经发育障碍儿童的 20,248 个家庭的全球数据库中进行了查询，这些家庭中父母的近亲结婚比例较高。这些家庭中大约三分之一的受影响儿童存在结构出生缺陷或小头畸形。我们对来自儿童、其父母或两者的样本进行外显子组或基因组测序，以识别在多个家庭中存在双等位基因致病性或可能致病性突变的基因。在确定致病变异后，我们生成了两个具有“敲入”致病性变异的小鼠模型，以研究机制并测试候选治疗方法。我们给怀孕动物施用小分子 Wnt 激动剂，并评估其后代。
我们在 5 个无关家庭的 10 名受影响者中发现了编码 Wnt 配体分泌介质（也称为 Wntless 或 WLS）的同源突变。（Wnt 配体分泌介质对于所有 Wnt 蛋白的分泌都是必不可少的。）患者有多种器官缺陷，包括小头畸形和面部畸形以及足并指畸形、肾发育不全、脱发、虹膜缺损和心脏缺陷。突变影响 WLS 蛋白稳定性和 Wnt 信号。敲入小鼠表现出与 Wnt 信号强度以及 Wnt 在胚胎发生中的个体和集体功能一致的组织和细胞脆弱性。施用药物 Wnt 激动剂部分恢复了胚胎发育。
影响中央 Wnt 调节剂的遗传变异导致综合征性结构出生缺陷。来自小鼠模型的结果表明，我们命名为 Zaki 综合征的疾病是一种潜在可预防的疾病。（由美国国立卫生研究院和其他机构资助）。
