RF09 | PSUN29 Evidence for a Founder Effect of SDHB Exon 1 Complete Deletion in Brazilian Patients with Paraganglioma
Authors: 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 
Published: November 2022

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.