SDHB exon 1 deletion: A recurrent germline mutation in Colombian patients with pheochromocytomas and paragangliomas

Abstract

Pheochromocytomas (PCCs) and paragangliomas (PGLs) (known as PPGL in combination) are rare neuroendocrine tumors of the adrenal medulla and extra-adrenal ganglia. About 40% of the patients with PPGL have a hereditary predisposition. Here we present a case-series of 19 unrelated Colombian patients with a clinical diagnosis of PPGL tumors that underwent germline genetic testing as part of the Hereditary Cancer Program developed at the Instituto Nacional de Cancerología, Colombia (INC-C), the largest reference cancer center in the country. Ten of 19 patients (52.63%) were identified as carriers of a pathogenic/likely pathogenic (P/LP) germline variant in a known susceptibility gene. The majority of the P/LP variants were in the SDHB gene (9/10): one corresponded to a nonsense variant c.268C>T (p.Arg90*) and eight cases were found to be carriers of a recurrent CNV consisting of a large deletion of one copy of exon 1, explaining 42% (8/19) of all the affected cases. Only one additional case was found to be a carrier of a missense mutation in the VHL gene: c.355T>C (p.Phe119Leu). Our study highlights the major role of SDHB in Colombian patients with a clinical diagnosis of PGL/PCC tumors and supports the recommendation of including the analysis of large deletions/duplications of the SDHB gene as part of the genetic counselling to improve the detection rate of hereditary cases and their clinical care.

Keywords: germline mutation; hereditary; human; neoplastic syndromes; paragangliomas; pheochromocytomas; succinate dehydrogenase subunit B.

FIGURE 1

Recurrent CNV in the SDHB gene in Colombians consisting in a large deletion of one copy of exon 1. (A) The graphic shows the copy number of the carrier (dots in color blue/red) and if it is similar (blue dots) or different (red dots) compared to the median of the copy numbers of each exon (1–8) among 8 different samples (gray dots) included in the same run. Graphic generated and extracted from SOPHIA Genetics. (B) Corresponding graphic obtained with MLPA confirmatory assay.