Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assay
BackgroundStickler syndrome (STL) is a group of related connective tissue disorders characterized by heterogeneous clinical presentations with varying degrees of orofacial, ocular, skeletal, and auditory abnormalities. However, this condition is difficult to diagnose on the basis of clinical feature...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2025.1642604/full |
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| author | Jie Zhang Jie Zhang Jie Zhang Yaxin Huang Yaxin Huang Yaxin Huang Yafei Deng Yafei Deng Yafei Deng Xiaochun Yang Hong Shi Yuecheng Yang Tao Lv Tao Lv Tao Lv Yuanlong Yan Yuanlong Yan Yuanlong Yan Ming He Fang Liu Fang Liu Fang Liu |
| author_facet | Jie Zhang Jie Zhang Jie Zhang Yaxin Huang Yaxin Huang Yaxin Huang Yafei Deng Yafei Deng Yafei Deng Xiaochun Yang Hong Shi Yuecheng Yang Tao Lv Tao Lv Tao Lv Yuanlong Yan Yuanlong Yan Yuanlong Yan Ming He Fang Liu Fang Liu Fang Liu |
| author_sort | Jie Zhang |
| collection | DOAJ |
| description | BackgroundStickler syndrome (STL) is a group of related connective tissue disorders characterized by heterogeneous clinical presentations with varying degrees of orofacial, ocular, skeletal, and auditory abnormalities. However, this condition is difficult to diagnose on the basis of clinical features because of phenotypic variability. Thus, expanding the variant spectrum of this disease will aid in achieving a firm definitive diagnosis of STL.MethodsComprehensive examinations, including ophthalmology, otology, and orthopedic evaluations, were performed to identify the disease phenotype of the proband. Furthermore, whole-exome sequencing (WES) and Sanger sequencing were performed to identify the molecular basis of the disease. In silico analysis and a minigene splicing assay were conducted to verify the pathogenicity of the splice site variant. The clinical phenotypes of the reported STL patients were then reviewed.ResultsThe proband presented mild symptoms with early-onset high myopia and mild scoliosis. A novel de novo splicing variant (NM_080629.3: c.4069-1G>T), in the COL11A1 gene was identified in the proband via WES and confirmed via Sanger sequencing. Minigene splicing assays verified that this variant resulted in abnormal splicing of the COL11A1 transcripts because of the skipping of exon 54 and retention of 21 bp in intron 53. The literature review revealed that the most common phenotypes associated with STL type 2 include myopia and hearing impairment.ConclusionWe identified a novel acceptor splice site variant causing aberrant splicing of COL11A1. Our findings expand the variant spectrum of this gene and provide a precise genetic diagnosis of STL that could be helpful in genetic counseling, reproductive prevention, and treatment of long-term complications of this disorder. |
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| institution | Kabale University |
| issn | 1664-8021 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Genetics |
| spelling | doaj-art-8f0d380fd70c428cb9602426ce94007a2025-08-22T04:10:37ZengFrontiers Media S.A.Frontiers in Genetics1664-80212025-08-011610.3389/fgene.2025.16426041642604Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assayJie Zhang0Jie Zhang1Jie Zhang2Yaxin Huang3Yaxin Huang4Yaxin Huang5Yafei Deng6Yafei Deng7Yafei Deng8Xiaochun Yang9Hong Shi10Yuecheng Yang11Tao Lv12Tao Lv13Tao Lv14Yuanlong Yan15Yuanlong Yan16Yuanlong Yan17Ming He18Fang Liu19Fang Liu20Fang Liu21Medical School, Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, ChinaDepartment of Medical Genetics, The First People’s Hospital of Yunnan Province, Kunming, ChinaNational Health Commission Key Laboratory of Preconception Health Birth in Western China, The First People’s Hospital of Yunnan Province, Kunming, ChinaMedical School, Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, ChinaDepartment of Medical Genetics, The First People’s Hospital of Yunnan Province, Kunming, ChinaNational Health Commission Key Laboratory of Preconception Health Birth in Western China, The First People’s Hospital of Yunnan Province, Kunming, ChinaMedical School, Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, ChinaDepartment of Medical Genetics, The First People’s Hospital of Yunnan Province, Kunming, ChinaNational Health Commission Key Laboratory of Preconception Health Birth in Western China, The First People’s Hospital of Yunnan Province, Kunming, ChinaDepartment of Ophthalmology, The First People’s Hospital of Yunnan Province, Kunming, ChinaState Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, ChinaThe Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, ChinaMedical School, Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, ChinaDepartment of Medical Genetics, The First People’s Hospital of Yunnan Province, Kunming, ChinaNational Health Commission Key Laboratory of Preconception Health Birth in Western China, The First People’s Hospital of Yunnan Province, Kunming, ChinaMedical School, Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, ChinaDepartment of Medical Genetics, The First People’s Hospital of Yunnan Province, Kunming, ChinaNational Health Commission Key Laboratory of Preconception Health Birth in Western China, The First People’s Hospital of Yunnan Province, Kunming, ChinaDepartment of Biochemistry and Molecular Biology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan, ChinaMedical School, Kunming University of Science and Technology, The First People’s Hospital of Yunnan Province, Kunming, Yunnan, ChinaDepartment of Medical Genetics, The First People’s Hospital of Yunnan Province, Kunming, ChinaNational Health Commission Key Laboratory of Preconception Health Birth in Western China, The First People’s Hospital of Yunnan Province, Kunming, ChinaBackgroundStickler syndrome (STL) is a group of related connective tissue disorders characterized by heterogeneous clinical presentations with varying degrees of orofacial, ocular, skeletal, and auditory abnormalities. However, this condition is difficult to diagnose on the basis of clinical features because of phenotypic variability. Thus, expanding the variant spectrum of this disease will aid in achieving a firm definitive diagnosis of STL.MethodsComprehensive examinations, including ophthalmology, otology, and orthopedic evaluations, were performed to identify the disease phenotype of the proband. Furthermore, whole-exome sequencing (WES) and Sanger sequencing were performed to identify the molecular basis of the disease. In silico analysis and a minigene splicing assay were conducted to verify the pathogenicity of the splice site variant. The clinical phenotypes of the reported STL patients were then reviewed.ResultsThe proband presented mild symptoms with early-onset high myopia and mild scoliosis. A novel de novo splicing variant (NM_080629.3: c.4069-1G>T), in the COL11A1 gene was identified in the proband via WES and confirmed via Sanger sequencing. Minigene splicing assays verified that this variant resulted in abnormal splicing of the COL11A1 transcripts because of the skipping of exon 54 and retention of 21 bp in intron 53. The literature review revealed that the most common phenotypes associated with STL type 2 include myopia and hearing impairment.ConclusionWe identified a novel acceptor splice site variant causing aberrant splicing of COL11A1. Our findings expand the variant spectrum of this gene and provide a precise genetic diagnosis of STL that could be helpful in genetic counseling, reproductive prevention, and treatment of long-term complications of this disorder.https://www.frontiersin.org/articles/10.3389/fgene.2025.1642604/fullde novo novel splicing variantwhole-exome sequencingminigene splicing assayCOL11A1 geneStickler syndrome |
| spellingShingle | Jie Zhang Jie Zhang Jie Zhang Yaxin Huang Yaxin Huang Yaxin Huang Yafei Deng Yafei Deng Yafei Deng Xiaochun Yang Hong Shi Yuecheng Yang Tao Lv Tao Lv Tao Lv Yuanlong Yan Yuanlong Yan Yuanlong Yan Ming He Fang Liu Fang Liu Fang Liu Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assay Frontiers in Genetics de novo novel splicing variant whole-exome sequencing minigene splicing assay COL11A1 gene Stickler syndrome |
| title | Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assay |
| title_full | Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assay |
| title_fullStr | Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assay |
| title_full_unstemmed | Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assay |
| title_short | Novel pathogenic splicing mutation in COL11A1 in a patient with Stickler syndrome verified by minigene splicing assay |
| title_sort | novel pathogenic splicing mutation in col11a1 in a patient with stickler syndrome verified by minigene splicing assay |
| topic | de novo novel splicing variant whole-exome sequencing minigene splicing assay COL11A1 gene Stickler syndrome |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2025.1642604/full |
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