Evidence for a Founder Effect of SDHB Exon 1 Deletion in Brazilian Patients With Paraganglioma

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Fagundes, Gustavo F. C. ; Freitas-Castro, Felipe ; Santana, Lucas S. ; Afonso, Ana Caroline F. ; Petenuci, Janaina ; Funari, Mariana F. A. ; Guimaraes, Augusto G. ; Ledesma, Felipe L. ; Pereira, Maria Adelaide A. ; Victor, Carolina R. ; Ferrari, Marcela S. M. ; Coelho, Fernando M. A. ; Srougi, Victor ; Tanno, Fabio Y. ; Chambo, Jose L. ; Latronico, Ana Claudia ; Mendonca, Berenice B. ; Fragoso, Maria Candida B., V ; Hoff, Ana O. ; Almeida, Madson Q.

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. N/A, p. 10-pg., 2023-01-18.

Abstract

Context Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X-2 = 29.43; P < 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas. (AU)

• FAPESP's process: 19/15873-6 - Investigation of new genetic, clinical and pathological aspects of endocrine arterial hypertension
• Grantee: Madson Queiroz Almeida
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/10101-5 - Investigation of novel genetic alterations associated with the pathogenesis of Aldosteronomas by exome sequencing
• Grantee: Augusto Garcia Guimarães
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 21/11240-9 - Whole exome sequencing for the investigation of novel genetic causes of metastatic Pheochromocytomas and Paragangliomas
• Grantee: Felipe Freitas de Castro
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/10363-0 - Whole exome sequencing for investigation of novel genetic causes of primary Aldosteronism caused by bilateral adrenal hyperplasia
• Grantee: Lucas Santos de Santana
• Support Opportunities: Scholarships in Brazil - Post-Doctoral