A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis
BackgroundNeurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder characterized by café-au-lait macules, neurofibromas, and other manifestations. It is caused by variations in the NF1 gene located on chromosome 17q11.2. The gene’s complexity and extensive variations often lead...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Genetics |
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| author | Tao Lin Zheyan Chen Biwen Dong Haojie Pan Hai Wang Xianjue Zheng Kaixin Chen Yanan Lai Chenhui Zhang Ye Dong Zitong Xu Menmen Lin Xiujie Xi Shuqi Xia Yimin Wang Wenhan Wang Xiaoqing Li Congcong Sun Yanjun Hu Fang Xu Jianqiong Zheng Fan Jin Hongping Zhang Hongping Zhang Jiayong Zheng Jiayong Zheng |
| author_facet | Tao Lin Zheyan Chen Biwen Dong Haojie Pan Hai Wang Xianjue Zheng Kaixin Chen Yanan Lai Chenhui Zhang Ye Dong Zitong Xu Menmen Lin Xiujie Xi Shuqi Xia Yimin Wang Wenhan Wang Xiaoqing Li Congcong Sun Yanjun Hu Fang Xu Jianqiong Zheng Fan Jin Hongping Zhang Hongping Zhang Jiayong Zheng Jiayong Zheng |
| author_sort | Tao Lin |
| collection | DOAJ |
| description | BackgroundNeurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder characterized by café-au-lait macules, neurofibromas, and other manifestations. It is caused by variations in the NF1 gene located on chromosome 17q11.2. The gene’s complexity and extensive variations often lead to misdiagnoses by conventional detection methods, which adverses to effective diagnosis and treatment strategies.Case presentationA 26-year-old Chinese woman was admitted to our hospital with multiple café-au-lait spots and cutaneous nodules. She had a family history of NF1, with her mother also showing similar dermatological symptoms. Whole exome sequencing (WES) identified a synonymous variation, NM_001042492.3: c.987A>G (p.K329K), in the NF1 gene. Although synonymous variations are typically considered non-pathogenic, RNA sequencing (RNA-seq) and minigene analysis revealed that this variation caused the partial loss of exon 9, leading to aberrant splicing. These findings were validated through Sanger sequencing, confirming the genetic alteration and its impact on mRNA splicing.ConclusionThe case highlights the critical role of synonymous variations in the NF1 gene that significantly impact splicing and protein function. These findings expand our understanding of NF1’s genetic diversity and underscore the importance of comprehensive genetic and RNA analyses to achieve accurate diagnosis and in-depth insight into the molecular underpinnings of NF1. |
| format | Article |
| id | doaj-art-e8f44ed52a6e47c3bb2e8f3bdd7bc9ba |
| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj-art-e8f44ed52a6e47c3bb2e8f3bdd7bc9ba2025-08-20T03:53:07ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-05-011610.3389/fgene.2025.15724871572487A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesisTao Lin0Zheyan Chen1Biwen Dong2Haojie Pan3Hai Wang4Xianjue Zheng5Kaixin Chen6Yanan Lai7Chenhui Zhang8Ye Dong9Zitong Xu10Menmen Lin11Xiujie Xi12Shuqi Xia13Yimin Wang14Wenhan Wang15Xiaoqing Li16Congcong Sun17Yanjun Hu18Fang Xu19Jianqiong Zheng20Fan Jin21Hongping Zhang22Hongping Zhang23Jiayong Zheng24Jiayong Zheng25Department of Gynecology and Obstetrics, Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Plastic and Aesthetic Surgery, Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaWenzhou City Key Laboratory of Gynecology and Obstetrics, Wenzhou, Zhejiang, ChinaWenzhou City Key Laboratory of Gynecology and Obstetrics, Wenzhou, Zhejiang, ChinaWenzhou City Key Laboratory of Gynecology and Obstetrics, Wenzhou, Zhejiang, ChinaDepartment of Gynecology and Obstetrics, Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Gynecology and Obstetrics, Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Gynecology and Obstetrics, Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaDepartment of Reproductive Genetics, Women’s Hospital, Zhejiang University School of Medicine, Hanzhou, ChinaDepartment of Gynecology and Obstetrics, Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaWenzhou City Key Laboratory of Gynecology and Obstetrics, Wenzhou, Zhejiang, ChinaDepartment of Reproductive Genetics, Wenzhou Third Clinical Institute Affiliated to Wenzhou Medical University/The Third Affiliated Hospital of Shanghai University/Wenzhou People’s Hospital/Wenzhou Maternal and Child Healthcare Hospital, Wenzhou, ChinaWenzhou City Key Laboratory of Gynecology and Obstetrics, Wenzhou, Zhejiang, ChinaBackgroundNeurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder characterized by café-au-lait macules, neurofibromas, and other manifestations. It is caused by variations in the NF1 gene located on chromosome 17q11.2. The gene’s complexity and extensive variations often lead to misdiagnoses by conventional detection methods, which adverses to effective diagnosis and treatment strategies.Case presentationA 26-year-old Chinese woman was admitted to our hospital with multiple café-au-lait spots and cutaneous nodules. She had a family history of NF1, with her mother also showing similar dermatological symptoms. Whole exome sequencing (WES) identified a synonymous variation, NM_001042492.3: c.987A>G (p.K329K), in the NF1 gene. Although synonymous variations are typically considered non-pathogenic, RNA sequencing (RNA-seq) and minigene analysis revealed that this variation caused the partial loss of exon 9, leading to aberrant splicing. These findings were validated through Sanger sequencing, confirming the genetic alteration and its impact on mRNA splicing.ConclusionThe case highlights the critical role of synonymous variations in the NF1 gene that significantly impact splicing and protein function. These findings expand our understanding of NF1’s genetic diversity and underscore the importance of comprehensive genetic and RNA analyses to achieve accurate diagnosis and in-depth insight into the molecular underpinnings of NF1.https://www.frontiersin.org/articles/10.3389/fgene.2025.1572487/fullneurofibromatosis type 1NF1synonymous variationsplicing variantwhole-exome sequencing |
| spellingShingle | Tao Lin Zheyan Chen Biwen Dong Haojie Pan Hai Wang Xianjue Zheng Kaixin Chen Yanan Lai Chenhui Zhang Ye Dong Zitong Xu Menmen Lin Xiujie Xi Shuqi Xia Yimin Wang Wenhan Wang Xiaoqing Li Congcong Sun Yanjun Hu Fang Xu Jianqiong Zheng Fan Jin Hongping Zhang Hongping Zhang Jiayong Zheng Jiayong Zheng A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis Frontiers in Genetics neurofibromatosis type 1 NF1 synonymous variation splicing variant whole-exome sequencing |
| title | A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis |
| title_full | A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis |
| title_fullStr | A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis |
| title_full_unstemmed | A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis |
| title_short | A novel synonymous variant in the NF1 gene disrupting splicing contributes to neurofibromatosis pathogenesis |
| title_sort | novel synonymous variant in the nf1 gene disrupting splicing contributes to neurofibromatosis pathogenesis |
| topic | neurofibromatosis type 1 NF1 synonymous variation splicing variant whole-exome sequencing |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1572487/full |
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