Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation
We aim to report the ocular phenotype and molecular genetic findings in two Czech families with Sorsby fundus dystrophy and to review all the reported <i>TIMP3</i> pathogenic variants. Two probands with Sorsby fundus dystrophy and three first-degree relatives underwent ocular examination...
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| Format: | Article |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/7/3744 |
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| author | Andrea Vergaro Monika Pankievic Jana Jedlickova Lubica Dudakova Marie Vajter Michel Michaelides Martin Meliska Pavel Nemec Daniela Babincova Bohdan Kousal Petra Liskova |
| author_facet | Andrea Vergaro Monika Pankievic Jana Jedlickova Lubica Dudakova Marie Vajter Michel Michaelides Martin Meliska Pavel Nemec Daniela Babincova Bohdan Kousal Petra Liskova |
| author_sort | Andrea Vergaro |
| collection | DOAJ |
| description | We aim to report the ocular phenotype and molecular genetic findings in two Czech families with Sorsby fundus dystrophy and to review all the reported <i>TIMP3</i> pathogenic variants. Two probands with Sorsby fundus dystrophy and three first-degree relatives underwent ocular examination and retinal imaging, including optical coherence tomography angiography. The DNA of the first proband was screened using a targeted ocular gene panel, while, in the second proband, direct sequencing of the <i>TIMP3</i> coding region was performed. Sanger sequencing was also used for segregation analysis within the families. All the previously reported <i>TIMP3</i> variants were reviewed using the American College of Medical Genetics and the Association for Molecular Pathology interpretation framework. A novel heterozygous variant, c.455A>G p.(Tyr152Cys), in <i>TIMP3</i> was identified in both families and potentially de novo in one. Optical coherence tomography angiography documented in one patient the development of a choroidal neovascular membrane at 54 years. Including this study, 23 heterozygous variants in <i>TIMP3</i> have been reported as disease-causing. Application of gene-specific criteria denoted eleven variants as pathogenic, eleven as likely pathogenic, and one as a variant of unknown significance. Our study expands the spectrum of <i>TIMP3</i> pathogenic variants and highlights the importance of optical coherence tomography angiography for early detection of choroidal neovascular membranes. |
| first_indexed | 2024-04-24T10:43:39Z |
| format | Article |
| id | doaj.art-b2520c6b1e1842d890582bce5d1ea665 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T10:43:39Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b2520c6b1e1842d890582bce5d1ea6652024-04-12T13:19:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01257374410.3390/ijms25073744Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) MutationAndrea Vergaro0Monika Pankievic1Jana Jedlickova2Lubica Dudakova3Marie Vajter4Michel Michaelides5Martin Meliska6Pavel Nemec7Daniela Babincova8Bohdan Kousal9Petra Liskova10Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 121 08 Prague, Czech RepublicDepartment of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 121 08 Prague, Czech RepublicDepartment of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 121 08 Prague, Czech RepublicDepartment of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 121 08 Prague, Czech RepublicDepartment of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 121 08 Prague, Czech RepublicUCL Institute of Ophthalmology, University College London and Moorfields Eye Hospital, London EC1V 9EL, UKDepartment of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech RepublicDepartment of Ophthalmology, First Faculty of Medicine and Military University Hospital Prague, 162 00 Prague, Czech RepublicLaboratory of Molecular Biology, AGEL, 741 01 Nový Jíčín, Czech RepublicDepartment of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 08 Prague, Czech RepublicDepartment of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, 121 08 Prague, Czech RepublicWe aim to report the ocular phenotype and molecular genetic findings in two Czech families with Sorsby fundus dystrophy and to review all the reported <i>TIMP3</i> pathogenic variants. Two probands with Sorsby fundus dystrophy and three first-degree relatives underwent ocular examination and retinal imaging, including optical coherence tomography angiography. The DNA of the first proband was screened using a targeted ocular gene panel, while, in the second proband, direct sequencing of the <i>TIMP3</i> coding region was performed. Sanger sequencing was also used for segregation analysis within the families. All the previously reported <i>TIMP3</i> variants were reviewed using the American College of Medical Genetics and the Association for Molecular Pathology interpretation framework. A novel heterozygous variant, c.455A>G p.(Tyr152Cys), in <i>TIMP3</i> was identified in both families and potentially de novo in one. Optical coherence tomography angiography documented in one patient the development of a choroidal neovascular membrane at 54 years. Including this study, 23 heterozygous variants in <i>TIMP3</i> have been reported as disease-causing. Application of gene-specific criteria denoted eleven variants as pathogenic, eleven as likely pathogenic, and one as a variant of unknown significance. Our study expands the spectrum of <i>TIMP3</i> pathogenic variants and highlights the importance of optical coherence tomography angiography for early detection of choroidal neovascular membranes.https://www.mdpi.com/1422-0067/25/7/3744Sorsby fundus dystrophychoroidal neovascular membraneTIMP3pathogenic variantsoptical coherence tomography angiography |
| spellingShingle | Andrea Vergaro Monika Pankievic Jana Jedlickova Lubica Dudakova Marie Vajter Michel Michaelides Martin Meliska Pavel Nemec Daniela Babincova Bohdan Kousal Petra Liskova Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation International Journal of Molecular Sciences Sorsby fundus dystrophy choroidal neovascular membrane TIMP3 pathogenic variants optical coherence tomography angiography |
| title | Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation |
| title_full | Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation |
| title_fullStr | Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation |
| title_full_unstemmed | Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation |
| title_short | Disease-Causing <i>TIMP3</i> Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation |
| title_sort | disease causing i timp3 i variants and deep phenotyping of two czech families with sorsby fundus dystrophy associated with novel p tyr152cys mutation |
| topic | Sorsby fundus dystrophy choroidal neovascular membrane TIMP3 pathogenic variants optical coherence tomography angiography |
| url | https://www.mdpi.com/1422-0067/25/7/3744 |
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