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Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations

by 1,2,3,4,†, 3,4,5,†, 1,2,3,4, 3,5, 1,2,3,4, 1,2,3,4, 2,3,4,5, 1,2,3,4, 3,5, 3,5, 1,2,4,5, 2,3,4,5 and 1,2,4,5,*
1
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
2
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China
3
Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
4
Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing 100730, China
5
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
*
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Academic Editors: A. J. Agopian and Jennifer E. Posey
Received: 24 August 2021 / Revised: 7 October 2021 / Accepted: 10 October 2021 / Published: 14 October 2021
(This article belongs to the Special Issue New Insights into Genetic Risk Assessment in Congenital Diseases)
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. View Full-Text
Keywords: congenital vertebral malformation; exome sequencing; NADSYN1 gene; congenital NAD Deficiency Disorder congenital vertebral malformation; exome sequencing; NADSYN1 gene; congenital NAD Deficiency Disorder
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MDPI and ACS Style

Lin, J.; Zhao, L.; Zhao, S.; Li, S.; Zhao, Z.; Chen, Z.; Zheng, Z.; Shao, J.; Niu, Y.; Li, X.; Zhang, J.T.; Wu, Z.; Wu, N. Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations. Genes 2021, 12, 1615. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101615

AMA Style

Lin J, Zhao L, Zhao S, Li S, Zhao Z, Chen Z, Zheng Z, Shao J, Niu Y, Li X, Zhang JT, Wu Z, Wu N. Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations. Genes. 2021; 12(10):1615. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101615

Chicago/Turabian Style

Lin, Jiachen, Lina Zhao, Sen Zhao, Shengjie Li, Zhengye Zhao, Zefu Chen, Zhifa Zheng, Jiashen Shao, Yuchen Niu, Xiaoxin Li, Jianguo T. Zhang, Zhihong Wu, and Nan Wu. 2021. "Disruptive NADSYN1 Variants Implicated in Congenital Vertebral Malformations" Genes 12, no. 10: 1615. https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101615

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