Poster Presentation 5th International Symposium on Phaeochromocytoma and Paraganglioma 2017

SDHA p.Arg31* is pathogenic but subpenetrant (#83)

Catherine Luxford 1 2 , Anne Louise Richardson 1 , Edward Kim 1 2 , Talia Novos 3 , Trish Dwight 1 2 , Diana (Dindy) Benn 1 2 , Katherine Tucker 4 , Bruce Robinson 1 2 5 , Chris White 3 , Anthony Gill 2 6 , Michael Field 7 , Roderick Clifton-Bligh 1 2 5
  1. Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia
  2. University of Sydney, Camperdown, NSW, Australia
  3. SEALS North, Department of Clinical Chemistry, Prince of Wales Hospital, Randwick, NSW, Australia
  4. Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, Australia
  5. Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW, Australia
  6. Cancer Diagnosis and Pathology Group, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia
  7. Northern Sydney Local Health District Familial Cancer Service, Department of Cancer Services, Royal North Shore Hospital, St Leonards, NSW, Australia

  1. Germline and somatic pathogenic SDHA variants have been associated with phaeochromocytomas and paragangliomas (PC/PGL)1.

    The variant SDHA c.91C>T predicts premature truncation at codon 31 (p.Arg31*) and is predicted by in silico tools to cause loss of normal protein function (either through protein truncation or nonsense-mediated mRNA decay).

    This nonsense variant has been reported in rare individuals with PC/PGL, gastrointestinal stromal tumors (GIST), Carney triad and some non-PGL tumours1,2,3,4,5,6. It is also present in the Exome Aggregation Consortium (ExAC) at a frequency of 0.00017 (1/5882), which would predict that it has low penetrance.

    We have identified 2 patients (with paragangliomas) carrying the heterozygous germline SDHA c.91C>T, (p.Arg31*) variant. The tumours from these cases demonstrated loss of immunohistochemical staining for both SDHB and SDHA, and metabolomic analysis also confirmed markedly elevated succinate:fumarate ratios (patient 1, 997 ± 320 [n=6]; patient 2, 155 [n=1]), consistent with SDH deficiency.

    Our data supports the hypothesis of the variant SDHA c.91C>T being pathogenic but of very low penetrance, possibly due to low rates of somatic SDHA inactivation (i.e. LOH). We propose that probands identified with this variant be followed closely for recurrent disease, but that cascade testing of family members should acknowledge the low likelihood of PC/PGL development in asymptomatic carriers.

  1. 1.Dénes et al., 2015 2.Korpershoek et al., 2011 3.Rattenberry et al., 2013 4.Pantaleo et al., 2011 5.Niemeijer et al., 2015 6.Boikos et al., 2016