A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencing
Abstract Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non‐coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes R...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202216478 |
| _version_ | 1797285810682200064 |
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| author | Nasrinsadat Nabavizadeh Annkatrin Bressin Mohammad Shboul Ricardo Moreno Traspas Poh Hui Chia Carine Bonnard Emmanuelle Szenker‐Ravi Burak Sarıbaş Emmanuel Beillard Umut Altunoglu Zohreh Hojati Scott Drutman Susanne Freier Mohammad El‐Khateeb Rajaa Fathallah Jean‐Laurent Casanova Wesam Soror Alaa Arafat Nathalie Escande‐Beillard Andreas Mayer Bruno Reversade |
| author_facet | Nasrinsadat Nabavizadeh Annkatrin Bressin Mohammad Shboul Ricardo Moreno Traspas Poh Hui Chia Carine Bonnard Emmanuelle Szenker‐Ravi Burak Sarıbaş Emmanuel Beillard Umut Altunoglu Zohreh Hojati Scott Drutman Susanne Freier Mohammad El‐Khateeb Rajaa Fathallah Jean‐Laurent Casanova Wesam Soror Alaa Arafat Nathalie Escande‐Beillard Andreas Mayer Bruno Reversade |
| author_sort | Nasrinsadat Nabavizadeh |
| collection | DOAJ |
| description | Abstract Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non‐coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA‐seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA‐seq, we delineated a deep intronic TAPT1 mutation (c.1237‐52 G>A) that segregated with the disease. Using SI‐NET‐seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre‐mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein‐null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease‐relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non‐coding variants, as well as in illuminating the molecular mechanisms of human diseases. |
| first_indexed | 2024-03-07T18:07:39Z |
| format | Article |
| id | doaj.art-921d307af59a483894117f4547a0983f |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:07:39Z |
| publishDate | 2023-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-921d307af59a483894117f4547a0983f2024-03-02T08:15:14ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-02-01152n/an/a10.15252/emmm.202216478A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencingNasrinsadat Nabavizadeh0Annkatrin Bressin1Mohammad Shboul2Ricardo Moreno Traspas3Poh Hui Chia4Carine Bonnard5Emmanuelle Szenker‐Ravi6Burak Sarıbaş7Emmanuel Beillard8Umut Altunoglu9Zohreh Hojati10Scott Drutman11Susanne Freier12Mohammad El‐Khateeb13Rajaa Fathallah14Jean‐Laurent Casanova15Wesam Soror16Alaa Arafat17Nathalie Escande‐Beillard18Andreas Mayer19Bruno Reversade20Laboratory of Human Genetics & Therapeutics Genome Institute of Singapore, A*STAR Singapore City SingaporeMax Planck Institute for Molecular Genetics Berlin GermanyDepartment of Medical Laboratory Sciences Jordan University of Science and Technology Irbid JordanLaboratory of Human Genetics & Therapeutics Genome Institute of Singapore, A*STAR Singapore City SingaporeLaboratory of Human Genetics & Therapeutics Genome Institute of Singapore, A*STAR Singapore City SingaporeModel Development, A*STAR Skin Research Labs (A*SRL) Singapore City SingaporeLaboratory of Human Genetics & Therapeutics Genome Institute of Singapore, A*STAR Singapore City SingaporeLaboratory of Human Genetics & Therapeutics Genome Institute of Singapore, A*STAR Singapore City SingaporeDepartment of Biopathology Centre Léon Bérard Lyon FranceMedical Genetics Department Koç University School of Medicine Istanbul TurkeyDivision of Genetics, Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology University of Isfahan Isfahan IranSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch Rockefeller University New York NY USAMax Planck Institute for Molecular Genetics Berlin GermanyNational Center for Diabetes, Endocrinology and Genetics Amman JordanNational Center for Diabetes, Endocrinology and Genetics Amman JordanSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch Rockefeller University New York NY USANational Center for Diabetes, Endocrinology and Genetics Amman JordanNational Center for Diabetes, Endocrinology and Genetics Amman JordanMedical Genetics Department Koç University School of Medicine Istanbul TurkeyMax Planck Institute for Molecular Genetics Berlin GermanyLaboratory of Human Genetics & Therapeutics Genome Institute of Singapore, A*STAR Singapore City SingaporeAbstract Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non‐coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA‐seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA‐seq, we delineated a deep intronic TAPT1 mutation (c.1237‐52 G>A) that segregated with the disease. Using SI‐NET‐seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre‐mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein‐null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease‐relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non‐coding variants, as well as in illuminating the molecular mechanisms of human diseases.https://doi.org/10.15252/emmm.202216478non‐coding variantOsteogenesis ImperfectaRNA‐seqSI‐NET‐seqTAPT1 |
| spellingShingle | Nasrinsadat Nabavizadeh Annkatrin Bressin Mohammad Shboul Ricardo Moreno Traspas Poh Hui Chia Carine Bonnard Emmanuelle Szenker‐Ravi Burak Sarıbaş Emmanuel Beillard Umut Altunoglu Zohreh Hojati Scott Drutman Susanne Freier Mohammad El‐Khateeb Rajaa Fathallah Jean‐Laurent Casanova Wesam Soror Alaa Arafat Nathalie Escande‐Beillard Andreas Mayer Bruno Reversade A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencing EMBO Molecular Medicine non‐coding variant Osteogenesis Imperfecta RNA‐seq SI‐NET‐seq TAPT1 |
| title | A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencing |
| title_full | A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencing |
| title_fullStr | A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencing |
| title_full_unstemmed | A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencing |
| title_short | A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI‐NET sequencing |
| title_sort | progeroid syndrome caused by a deep intronic variant in tapt1 is revealed by rna si net sequencing |
| topic | non‐coding variant Osteogenesis Imperfecta RNA‐seq SI‐NET‐seq TAPT1 |
| url | https://doi.org/10.15252/emmm.202216478 |
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