{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:14:28Z","timestamp":1792804468699,"version":"4.5.0"},"reference-count":27,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81822030, 82072391, 81930068, 81772299, 81672123, 81972037"],"award-info":[{"award-number":["81822030, 82072391, 81930068, 81772299, 81672123, 81972037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["JQ20032, 7191007, L192015"],"award-info":[{"award-number":["JQ20032, 7191007, L192015"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Capital\u2019s Funds for Health Improvement and Research","award":["2020-4-40114"],"award-info":[{"award-number":["2020-4-40114"]}]},{"name":"Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences","award":["2019PT320025"],"award-info":[{"award-number":["2019PT320025"]}],"id":[{"id":"https:\/\/ror.org\/02drdmm93","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"https:\/\/ror.org\/04jztag35","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Genetic perturbations in nicotinamide adenine dinucleotide de novo (NAD) synthesis pathway predispose individuals to congenital birth defects. The NADSYN1 encodes the final enzyme in the de novo NAD synthesis pathway and, therefore, plays an important role in NAD metabolism and organ embryogenesis. Biallelic mutations in the NADSYN1 gene have been reported to be causative of congenital organ defects known as VCRL syndrome (Vertebral-Cardiac-Renal-Limb syndrome). Here, we analyzed the genetic variants in NADSYN1 in an exome-sequenced cohort consisting of patients with congenital vertebral malformations (CVMs). A total number of eight variants in NADSYN1, including two truncating variants and six missense variants, were identified in nine unrelated patients. All enrolled patients presented multiple organ defects, with the involvement of either the heart, kidney, limbs, or liver, as well as intraspinal deformities. An in vitro assay using COS-7 cells demonstrated either significantly reduced protein levels or disrupted enzymatic activity of the identified variants. Our findings demonstrated that functional variants in NADSYN1 were involved in the complex genetic etiology of CVMs and provided further evidence for the causative NADSYN1 variants in congenital NAD Deficiency Disorder.<\/jats:p>","DOI":"10.3390\/genes12101615","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T09:10:49Z","timestamp":1634202649000},"page":"1615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations"],"prefix":"10.3390","volume":"12","author":[{"given":"Jiachen","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhao","sequence":"additional","affiliation":[{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjie","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengye","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zefu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifa","family":"Zheng","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiashen","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Niu","sequence":"additional","affiliation":[{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"Li","sequence":"additional","affiliation":[{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3129-5190","authenticated-orcid":false,"given":"Jianguo Terry","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-2889","authenticated-orcid":false,"given":"Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China"},{"name":"Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China"},{"name":"State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1136\/jmg.12.3.280","article-title":"Congenital vertebral anomalies: Aetiology and relationship to spina bifida cystica","volume":"12","year":"1975","journal-title":"J. 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Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.cell.2012.02.054","article-title":"A mechanism for gene-environment interaction in the etiology of congenital scoliosis","volume":"149","author":"Sparrow","year":"2012","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1038\/s41436-018-0377-x","article-title":"TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: Further evidence supporting the compound inheritance and TBX6 gene dosage model","volume":"21","author":"Liu","year":"2019","journal-title":"Genet. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1002\/humu.23907","article-title":"TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease","volume":"41","author":"Chen","year":"2020","journal-title":"Hum. 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