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RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma
BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) have the highest degree of heritability among endocrine tumors. Currently, ∼40% of PPGL individuals have a genetic germline pathogenic variant and exist at least 12 different genetic syndromes related to these tumors. Pathogenic variants in th...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629149/ http://dx.doi.org/10.1210/jendso/bvac150.273 |
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author | Fagundes, Gustavo F Almeida, Madson Q Santana, Lucas Castro, Felipe Afonso, Ana Caroline Petenuci, Janaina Funari, Mariana Guimarães, Augusto G Sales, Elaine V Vieites, Ana Sanso, Gabriela Ledesma, Felipe L Siqueira, Sheila Pereira, Maria Adelaide A Tanno, Fabio Y Srougi, Vitor Chambo, Jose L Victor, Carolina R Ferrari, Marcela S Coelho, Fernando M Soares, Silvia C Latronico, Ana Claudia Mendonca, Berenice B Fragoso, Maria Candida BV Hoff, Ana O |
author_facet | Fagundes, Gustavo F Almeida, Madson Q Santana, Lucas Castro, Felipe Afonso, Ana Caroline Petenuci, Janaina Funari, Mariana Guimarães, Augusto G Sales, Elaine V Vieites, Ana Sanso, Gabriela Ledesma, Felipe L Siqueira, Sheila Pereira, Maria Adelaide A Tanno, Fabio Y Srougi, Vitor Chambo, Jose L Victor, Carolina R Ferrari, Marcela S Coelho, Fernando M Soares, Silvia C Latronico, Ana Claudia Mendonca, Berenice B Fragoso, Maria Candida BV Hoff, Ana O |
author_sort | Fagundes, Gustavo F |
collection | PubMed |
description | BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) have the highest degree of heritability among endocrine tumors. Currently, ∼40% of PPGL individuals have a genetic germline pathogenic variant and exist at least 12 different genetic syndromes related to these tumors. Pathogenic variants in the Succinate Dehydrogenase Complex Subunit B (SDHB) gene account for about 10% of PPGL cases. Moreover, SDHB pathogenic variants are the most well-established risk factor to predict metastatic disease (40%-50% of cases). Germline SDHB large deletions are very rare worldwide, but SDHB exon 1 deletion has been reported in patients with PPGLs from Portugal and Spain. Indeed, a putative founder effect for SDHB exon 1 deletion was suggested in PPGL patients from Iberian Peninsula. AIM: To investigate a putative founder effect for SDHB exon 1 deletion. METHODS: Eighteen unrelated Brazilian patients with germline heterozygous SDHB pathogenic variants were included. Additionally, two unrelated individuals with SDHB exon 1 complete deletion from Argentina were studied. SDHB pathogenic variants were investigated by automated SAGER sequencing, multiplex ligation-dependent probe amplification (SALSA MLPA Probemix P226 SDH) and/or high-throughput sequencing. Five SDHB flanking microsatellite markers at chromosome 1p (D1S2697, GATA29A05, D1S2826, D1S2644, and D1S199) were used to investigate if patients carrying this deletion have a common origin. Haplotypes were reconstructed using the PHASE algorithm (v. 2.1). A control group comprising 26 unrelated Brazilian individuals was also studied. RESULTS: Among 18 Brazilian patients with germline SDHB pathogenic variants, heterozygous SDHB exon 1 complete deletion was identified in 6 of them (33% of the cases). The remaining 12 patients presented intragenic SDHB pathogenic variants without hotspot location. All Brazilian index patients with SDHB exon 1 deletion presented with paraganglioma, located mostly in the abdomen (4 abdominal; one thoracic; two head and neck and one colonic). Median age was 31.5 years and metastatic disease occurred in 3 (50%) of them. Haplotype analysis showed that 4 apparently unrelated Brazilian patients (4 out of 6 cases, 67%) shared a common allele (SDHB-GATA29A05-D1S2826-D1S2644-D1S199 | SDHB-186-130-213-102), which was not seen in chromosomes without the SDHB exon 1 deletion (p= 0.01). The two cases from Argentina did not have this haplotype, suggesting that SDHB exon 1 deletion in Argentina have a different origin. CONCLUSION: SDHB exon 1 complete deletion was the most frequent SDHB defect in our cohort. Our findings indicate a founder effect for SDHB exon 1 complete deletion in Brazilian patients with paraganglioma. Support: Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6 Presentation: Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m. |
format | Online Article Text |
id | pubmed-9629149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-96291492022-11-04 RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma Fagundes, Gustavo F Almeida, Madson Q Santana, Lucas Castro, Felipe Afonso, Ana Caroline Petenuci, Janaina Funari, Mariana Guimarães, Augusto G Sales, Elaine V Vieites, Ana Sanso, Gabriela Ledesma, Felipe L Siqueira, Sheila Pereira, Maria Adelaide A Tanno, Fabio Y Srougi, Vitor Chambo, Jose L Victor, Carolina R Ferrari, Marcela S Coelho, Fernando M Soares, Silvia C Latronico, Ana Claudia Mendonca, Berenice B Fragoso, Maria Candida BV Hoff, Ana O J Endocr Soc Adrenal BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) have the highest degree of heritability among endocrine tumors. Currently, ∼40% of PPGL individuals have a genetic germline pathogenic variant and exist at least 12 different genetic syndromes related to these tumors. Pathogenic variants in the Succinate Dehydrogenase Complex Subunit B (SDHB) gene account for about 10% of PPGL cases. Moreover, SDHB pathogenic variants are the most well-established risk factor to predict metastatic disease (40%-50% of cases). Germline SDHB large deletions are very rare worldwide, but SDHB exon 1 deletion has been reported in patients with PPGLs from Portugal and Spain. Indeed, a putative founder effect for SDHB exon 1 deletion was suggested in PPGL patients from Iberian Peninsula. AIM: To investigate a putative founder effect for SDHB exon 1 deletion. METHODS: Eighteen unrelated Brazilian patients with germline heterozygous SDHB pathogenic variants were included. Additionally, two unrelated individuals with SDHB exon 1 complete deletion from Argentina were studied. SDHB pathogenic variants were investigated by automated SAGER sequencing, multiplex ligation-dependent probe amplification (SALSA MLPA Probemix P226 SDH) and/or high-throughput sequencing. Five SDHB flanking microsatellite markers at chromosome 1p (D1S2697, GATA29A05, D1S2826, D1S2644, and D1S199) were used to investigate if patients carrying this deletion have a common origin. Haplotypes were reconstructed using the PHASE algorithm (v. 2.1). A control group comprising 26 unrelated Brazilian individuals was also studied. RESULTS: Among 18 Brazilian patients with germline SDHB pathogenic variants, heterozygous SDHB exon 1 complete deletion was identified in 6 of them (33% of the cases). The remaining 12 patients presented intragenic SDHB pathogenic variants without hotspot location. All Brazilian index patients with SDHB exon 1 deletion presented with paraganglioma, located mostly in the abdomen (4 abdominal; one thoracic; two head and neck and one colonic). Median age was 31.5 years and metastatic disease occurred in 3 (50%) of them. Haplotype analysis showed that 4 apparently unrelated Brazilian patients (4 out of 6 cases, 67%) shared a common allele (SDHB-GATA29A05-D1S2826-D1S2644-D1S199 | SDHB-186-130-213-102), which was not seen in chromosomes without the SDHB exon 1 deletion (p= 0.01). The two cases from Argentina did not have this haplotype, suggesting that SDHB exon 1 deletion in Argentina have a different origin. CONCLUSION: SDHB exon 1 complete deletion was the most frequent SDHB defect in our cohort. Our findings indicate a founder effect for SDHB exon 1 complete deletion in Brazilian patients with paraganglioma. Support: Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6 Presentation: Saturday, June 11, 2022 1:24 p.m. - 1:29 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m. Oxford University Press 2022-11-01 /pmc/articles/PMC9629149/ http://dx.doi.org/10.1210/jendso/bvac150.273 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Adrenal Fagundes, Gustavo F Almeida, Madson Q Santana, Lucas Castro, Felipe Afonso, Ana Caroline Petenuci, Janaina Funari, Mariana Guimarães, Augusto G Sales, Elaine V Vieites, Ana Sanso, Gabriela Ledesma, Felipe L Siqueira, Sheila Pereira, Maria Adelaide A Tanno, Fabio Y Srougi, Vitor Chambo, Jose L Victor, Carolina R Ferrari, Marcela S Coelho, Fernando M Soares, Silvia C Latronico, Ana Claudia Mendonca, Berenice B Fragoso, Maria Candida BV Hoff, Ana O RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma |
title | RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma |
title_full | RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma |
title_fullStr | RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma |
title_full_unstemmed | RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma |
title_short | RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma |
title_sort | rf09 | psun29 evidence for a founder effect of sdhb exon 1 complete deletion in brazilian patients with paraganglioma |
topic | Adrenal |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9629149/ http://dx.doi.org/10.1210/jendso/bvac150.273 |
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