Yu Xu1, Yong-Biao Zhang2, Li-Jun Liang1, Jia-Li Tian1, Jin-Ming Lin3, Pan-Pan Wang3, Rong-Hui Li3, Ming-Liang Gu4,5, Zhan-Cheng Gao6. 1. Department of Pulmonary and Critical Care Medicine, Peking University People's Hospital, Beijing, 100044, People's Republic of China. 2. Interdisciplinary Innovation Institute of Medicine and Engineering, Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100109, People's Republic of China. 3. CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China. 4. CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China. minglianggu@hotmail.com. 5. Joint Laboratory for Translational Medicine Research, Beijing Institute of Genomics, Chinese Academy of Sciences and Liaocheng People's Hospital, Liaocheng City, 252000, Shandong Province, People's Republic of China. minglianggu@hotmail.com. 6. Department of Pulmonary and Critical Care Medicine, Peking University People's Hospital, Beijing, 100044, People's Republic of China. zcgao@bjmu.edu.cn.
Abstract
BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. METHODS: We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. RESULTS: After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. CONCLUSIONS: NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.
BACKGROUND:Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. METHODS: We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. RESULTS: After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. CONCLUSIONS:NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.
Authors: Cornelius J J Westermann; Ahlsen F Rosina; Vanessa De Vries; Pamela A de Coteau Journal: Am J Med Genet A Date: 2003-02-01 Impact factor: 2.802