Four unrelated families with familial HNPGLs were screened for germline mutations in the SDHB, SDHC and SDHD genes by direct sequencing. One hundred healthy subjects without a diagnosis or family history of HNPGLs were screened as normal controls. Immunohistochemistry with SDHB antibody was performed for a carotid body tumor.
Two allele variants were identified, including p.Met1Val (c.1A > G) in the SDHD gene in one family and p.Met1Ile (c.3G > C) in the SDHD gene in the other three families. Both variants are considered pathogenic because of the absence of these variants in 100 normal controls, 100 % evolutionary conservation of the p.Met1 residue, co-segregation of the variants with the phenotype of HNPGL in pedigrees, and predicted abolishment of the translation start site. The tumor cells obtained from one proband harboring c.3G > C mis-sense mutation were weak diffuse staining in the cytoplasm of tumors cells.
This study demonstrates that two mis-sense mutations at the start codon of the SDHD gene, including p.Met1Val (c.1A > G) and p.Met1Ile (c.3G > C), might be mutation hotspots in Chinese patients with familial HNPGLs.