Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastoma
Retinoblastoma (RB) is the most common primary intraocular malignancy in children and mostly initiates with biallelic inactivation of the RB1 gene. Hereditary retinoblastoma accounts for 40% of all cases, with only 6%–10% of patients having a positive family history. The proband, a Chinese Tibetan b...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1525035/full |
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| author | Guo-qian He Guo-qian He Ying-chun Zheng Lin-jun Tan Lin-jun Tan Cheng-qi Shen Cheng-qi Shen Ju Gao Ju Gao Fu Xiong Xia Guo Xia Guo |
| author_facet | Guo-qian He Guo-qian He Ying-chun Zheng Lin-jun Tan Lin-jun Tan Cheng-qi Shen Cheng-qi Shen Ju Gao Ju Gao Fu Xiong Xia Guo Xia Guo |
| author_sort | Guo-qian He |
| collection | DOAJ |
| description | Retinoblastoma (RB) is the most common primary intraocular malignancy in children and mostly initiates with biallelic inactivation of the RB1 gene. Hereditary retinoblastoma accounts for 40% of all cases, with only 6%–10% of patients having a positive family history. The proband, a Chinese Tibetan boy, was diagnosed with RB for leukocoria. The RB1 gene mutations were screened due to disease recurrence. A novel germline donor splicing site mutation (c.861 + 2T>A) from his father was identified by Sanger sequencing and a novel somatic duplication mutation in exon 2 221-224 (p.W75Cfs*36) by next-generation sequencing (NGS). The proband’s younger brother manifested bilateral RB and also carried the same germline mutation. To further explore the possible pathogenicity of the novel germline RB1 mutation (c.861 + 2T>A) in RB development, mutation analysis, bioinformatics analysis, and immunohistochemistry were performed. After RB1 cDNA was amplified, the abnormal script was found to be smaller than the normal script. Compared with normal samples, Sanger sequencing revealed a deletion of 143 bp in the abnormal script. In comparison to healthy individuals, patients exhibited a reduction in the mRNA expression levels of the RB1 gene. The three-dimensional structure predicted by iterative threading assembly refinement (I-TASSER) indicates significant changes in the spatial structure of abnormal proteins after mutation. No expression of RB1 was found in tumor tissue by immunohistochemistry evaluation. Therefore, the novel germline donor splicing site mutation (c.861 + 2T>A) has been confirmed to be a pathological mutation. |
| format | Article |
| id | doaj-art-2813eb1632b24ce79ea625e84ef0e3c5 |
| institution | DOAJ |
| issn | 2234-943X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj-art-2813eb1632b24ce79ea625e84ef0e3c52025-08-20T03:07:28ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2025-05-011510.3389/fonc.2025.15250351525035Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastomaGuo-qian He0Guo-qian He1Ying-chun Zheng2Lin-jun Tan3Lin-jun Tan4Cheng-qi Shen5Cheng-qi Shen6Ju Gao7Ju Gao8Fu Xiong9Xia Guo10Xia Guo11Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, ChinaDepartment of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, ChinaDepartment of Pediatrics, Affiliated Hospital of Zunyi Medical University, Zunyi, ChinaDepartment of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, ChinaKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, ChinaNHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, ChinaDepartment of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaDepartment of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, ChinaNHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, ChinaRetinoblastoma (RB) is the most common primary intraocular malignancy in children and mostly initiates with biallelic inactivation of the RB1 gene. Hereditary retinoblastoma accounts for 40% of all cases, with only 6%–10% of patients having a positive family history. The proband, a Chinese Tibetan boy, was diagnosed with RB for leukocoria. The RB1 gene mutations were screened due to disease recurrence. A novel germline donor splicing site mutation (c.861 + 2T>A) from his father was identified by Sanger sequencing and a novel somatic duplication mutation in exon 2 221-224 (p.W75Cfs*36) by next-generation sequencing (NGS). The proband’s younger brother manifested bilateral RB and also carried the same germline mutation. To further explore the possible pathogenicity of the novel germline RB1 mutation (c.861 + 2T>A) in RB development, mutation analysis, bioinformatics analysis, and immunohistochemistry were performed. After RB1 cDNA was amplified, the abnormal script was found to be smaller than the normal script. Compared with normal samples, Sanger sequencing revealed a deletion of 143 bp in the abnormal script. In comparison to healthy individuals, patients exhibited a reduction in the mRNA expression levels of the RB1 gene. The three-dimensional structure predicted by iterative threading assembly refinement (I-TASSER) indicates significant changes in the spatial structure of abnormal proteins after mutation. No expression of RB1 was found in tumor tissue by immunohistochemistry evaluation. Therefore, the novel germline donor splicing site mutation (c.861 + 2T>A) has been confirmed to be a pathological mutation.https://www.frontiersin.org/articles/10.3389/fonc.2025.1525035/fullretinoblastomaRB1 genedonor splicing site mutationgermlinechild |
| spellingShingle | Guo-qian He Guo-qian He Ying-chun Zheng Lin-jun Tan Lin-jun Tan Cheng-qi Shen Cheng-qi Shen Ju Gao Ju Gao Fu Xiong Xia Guo Xia Guo Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastoma Frontiers in Oncology retinoblastoma RB1 gene donor splicing site mutation germline child |
| title | Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastoma |
| title_full | Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastoma |
| title_fullStr | Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastoma |
| title_full_unstemmed | Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastoma |
| title_short | Case Report: A novel germline donor splicing site mutation of RB1 gene in a Chinese Tibetan pedigree with familial retinoblastoma |
| title_sort | case report a novel germline donor splicing site mutation of rb1 gene in a chinese tibetan pedigree with familial retinoblastoma |
| topic | retinoblastoma RB1 gene donor splicing site mutation germline child |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2025.1525035/full |
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