Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms
Abstract Objective Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or...
| Główni autorzy: | , , , , , , , |
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| Format: | Artykuł |
| Język: | English |
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BMC
2024-04-01
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| Seria: | BMC Medical Genomics |
| Hasła przedmiotowe: | |
| Dostęp online: | https://doi.org/10.1186/s12920-024-01858-y |
| _version_ | 1827276889786417152 |
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| author | Hui Zhang Jian Gao Hanjun Wang Mengli Liu Shuangshuang Lu Hongen Xu Wenxue Tang Guoxi Zheng |
| author_facet | Hui Zhang Jian Gao Hanjun Wang Mengli Liu Shuangshuang Lu Hongen Xu Wenxue Tang Guoxi Zheng |
| author_sort | Hui Zhang |
| collection | DOAJ |
| description | Abstract Objective Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or cysts, as well as renal abnormalities.This study aims to identify the pathogenic variants by performing genetic testing on a family with Branchio-oto-renal /Branchio-otic (BO, OMIM#602,588) syndrome using whole-exome sequencing, and to explore possible pathogenic mechanisms. Methods The family spans 4 generations and consists of 9 individuals, including 4 affected by the BOR/BO syndrome. Phenotypic information, including ear malformation and branchial cleft, was collected from family members. Audiological, temporal bone imaging, and renal ultrasound examinations were also performed. Whole-exome sequencing was conducted to identify candidate pathogenic variants and explore the underlying molecular etiology of BOR/BO syndrome by minigene experiments. Results Intra-familial variability was observed in the clinical phenotypes of BOR/BO syndrome in this family. The severity and nature of hearing loss varied in family members, with mixed or sensorineural hearing loss. The proband, in particular, had profound sensorineural hearing loss on the left and moderate conductive hearing loss on the right. Additionally, the proband exhibited developmental delay, and her mother experienced renal failure during pregnancy and terminated the pregnancy prematurely. Genetic testing revealed a novel heterozygous variant NM_000503.6: c.639 + 3 A > C in the EYA1 gene in affected family members. In vitro minigene experiments demonstrated its effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was classified as likely pathogenic. Conclusion This study highlights the phenotypic heterogeneity within the same family, reports the occurrence of renal failure and adverse pregnancy outcomes in a female patient at reproductive age with BOR syndrome, and enriches the mutational spectrum of pathogenic variants in the EYA1 gene. |
| first_indexed | 2024-04-24T07:10:37Z |
| format | Article |
| id | doaj.art-3af2a963f61941838169b602feab7d12 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-04-24T07:10:37Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-3af2a963f61941838169b602feab7d122024-04-21T11:33:17ZengBMCBMC Medical Genomics1755-87942024-04-011711910.1186/s12920-024-01858-yNovel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanismsHui Zhang0Jian Gao1Hanjun Wang2Mengli Liu3Shuangshuang Lu4Hongen Xu5Wenxue Tang6Guoxi Zheng7Department of Otorhinolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Xi’an Jiaotong UniversityNational Center for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversityBGI College and Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityPrecision Medicine Center, Academy of Medical Science, Zhengzhou UniversityNational Center for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou UniversityPrecision Medicine Center, Academy of Medical Science, Zhengzhou UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Zhengzhou UniversityDepartment of Otorhinolaryngology Head and Neck Surgery, the Second Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Objective Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or cysts, as well as renal abnormalities.This study aims to identify the pathogenic variants by performing genetic testing on a family with Branchio-oto-renal /Branchio-otic (BO, OMIM#602,588) syndrome using whole-exome sequencing, and to explore possible pathogenic mechanisms. Methods The family spans 4 generations and consists of 9 individuals, including 4 affected by the BOR/BO syndrome. Phenotypic information, including ear malformation and branchial cleft, was collected from family members. Audiological, temporal bone imaging, and renal ultrasound examinations were also performed. Whole-exome sequencing was conducted to identify candidate pathogenic variants and explore the underlying molecular etiology of BOR/BO syndrome by minigene experiments. Results Intra-familial variability was observed in the clinical phenotypes of BOR/BO syndrome in this family. The severity and nature of hearing loss varied in family members, with mixed or sensorineural hearing loss. The proband, in particular, had profound sensorineural hearing loss on the left and moderate conductive hearing loss on the right. Additionally, the proband exhibited developmental delay, and her mother experienced renal failure during pregnancy and terminated the pregnancy prematurely. Genetic testing revealed a novel heterozygous variant NM_000503.6: c.639 + 3 A > C in the EYA1 gene in affected family members. In vitro minigene experiments demonstrated its effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was classified as likely pathogenic. Conclusion This study highlights the phenotypic heterogeneity within the same family, reports the occurrence of renal failure and adverse pregnancy outcomes in a female patient at reproductive age with BOR syndrome, and enriches the mutational spectrum of pathogenic variants in the EYA1 gene.https://doi.org/10.1186/s12920-024-01858-yEYA1 geneBranchio-oto-renal syndromeWhole-exome sequencing |
| spellingShingle | Hui Zhang Jian Gao Hanjun Wang Mengli Liu Shuangshuang Lu Hongen Xu Wenxue Tang Guoxi Zheng Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms BMC Medical Genomics EYA1 gene Branchio-oto-renal syndrome Whole-exome sequencing |
| title | Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms |
| title_full | Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms |
| title_fullStr | Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms |
| title_full_unstemmed | Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms |
| title_short | Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms |
| title_sort | novel likely pathogenic variant in the eya1 gene causing branchio oto renal syndrome and the exploration of pathogenic mechanisms |
| topic | EYA1 gene Branchio-oto-renal syndrome Whole-exome sequencing |
| url | https://doi.org/10.1186/s12920-024-01858-y |
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