Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation

J Clin Endocrinol Metab. 2014 Jul;99(7):E1392-6. doi: 10.1210/jc.2013-4536. Epub 2014 Apr 8.

Abstract

Context: Hereditary pheochromocytoma/paraganglioma (PC/PGL) accounts for up to 60% of previously considered sporadic tumors. Guidelines suggest that phenotype should guide genetic testing. Next-generation sequencing technology can simultaneously sequence 9 of the 18 known susceptibility genes in a timely, cost-efficient manner.

Objective: Our aim was to confirm that universal screening is superior to targeted testing in patients with histologically confirmed PC and PGL.

Methods: In two tertiary referral hospitals in Ireland, NGS was carried out on all histologically confirmed cases of PC/PGL diagnosed between 2004 and 2013. The following susceptibility genes were sequenced: VHL, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX. A multiplex ligation-dependent probe amplification analysis was performed in VHL, SDHB, SDHC, SDHD, and SDHAF2 genes to detect deletions and duplications.

Results: A total of 31 patients were tested, 31% (n = 10) of whom were found to have a genetic mutation. Of those patients with a positive genotype, phenotype predicted genotype in only 50% (n = 5). Significant genetic mutations that would have been missed in our cohort by phenotypic evaluation alone include a mutation in TMEM127, two mutations in SDHAF2, and two mutations in RET. Target testing would have identified three of the latter mutations based on age criteria. However, 20% of patients (n = 2) would not have satisfied any criteria for targeted testing including one patient with a novel presentation of an SDHAF2 mutation.

Conclusion: This study supports the value of universal genetic screening for all patients with PC/PGL.

Publication types

  • Validation Study

MeSH terms

  • Adrenal Gland Neoplasms / epidemiology
  • Adrenal Gland Neoplasms / genetics*
  • Aged
  • Female
  • Genetic Association Studies
  • Genetic Testing / methods*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Mass Screening / methods
  • Middle Aged
  • Mitochondrial Proteins / genetics*
  • Multiplex Polymerase Chain Reaction
  • Mutation
  • Paraganglioma / epidemiology
  • Paraganglioma / genetics*
  • Pheochromocytoma / epidemiology
  • Pheochromocytoma / genetics*

Substances

  • Mitochondrial Proteins
  • SDHAF2 protein, human