Genotype-phenotype correlation in patients with germline mutations of VHL, RET, SDHB, and SDHD genes: Thai experience

Abstract

Mutations in the VHL, RET, SDHB, and SDHD genes are responsible for von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN2), and familial paraganglioma, respectively. However, genotype-phenotype correlation data are lacking in Southeast Asia. A retrospective medical chart review was performed on patients referred to the genetics service. We found 35 patients diagnosed with clinical syndromes (16 VHL, 9 MEN2, 9 paragangliomas, and 1 neurofibromatosis type 1). In patients with VHL, 5 known VHL mutations were identified: p.Trp88X, p.Ile151Thr, p.Arg161X, p.Arg167Gln, and p.Leu178Arg. The most frequent RET mutations in patients with MEN2A occurred at codon 634 on exon 11: p.Cys634Tyr, p.Cys634Trp, and p.Cys634Arg. A patient with MEN2B had p.Met918Thr RET mutation. Approximately, 90% of patients with MEN2 had medullary thyroid carcinoma. Pheochromocytoma was found in 55.6% of patients with MEN2, and 60% of them had bilateral lesions. One patient with malignant thoracic paraganglioma had p.Arg46X mutation of SDHB. This study provides mutation phenotypes that offer a useful tool for clinicians and patients to stratify disease risks and tailor screening programs.