P25: What are the clinical implications of SDHA pathogenic variants?

Friday, March 24, 2023

11:46 AM – 11:51 AM

Location: SSO HUB: Breast & Endocrine Zone

Poster Presenter(s)

Heather Wachtel, MD (she/her/hers)

Assistant Professor of Surgery
University of Pennsylvania
Philadelphia, Pennsylvania, United States

Disclosure(s): No financial relationships to disclose

Author(s)

Heather Wachtel, MD (she/her/hers)

Assistant Professor of Surgery
University of Pennsylvania
Philadelphia, Pennsylvania, United States

Disclosure(s): No financial relationships to disclose
SA

Stephanie Asher, MS CGC

Genetic Counselor
University of Pennsylvania, Medical Genetics, United States

Disclosure information not submitted.
AR

Anna Raper, MS CGC

Genetic Counselor
University of Pennsylvania, Medical Genetics, United States

Disclosure information not submitted.
MB

Maria Bonanni, CRNP

Nurse Practitioner
University of Pennsylvania, Medical Genetics, United States

Disclosure information not submitted.
EK

Emma Kennedy, MS CGC

Genetic Counselor
University of Pennsylvania, Medical Genetics, United States

Disclosure information not submitted.
RG

Regeneron Genetics Center, Regeneron Genetics Center

Regeneron Genetics Center
Regeneron Genetics Center, United States

Disclosure information not submitted.
KN

Katherine Nathanson, MD

Professor of Medical Genetics
University of Pennsylvania, Medical Genetics, United States

Disclosure information not submitted.

Disclosure(s):

Heather Wachtel, MD: No financial relationships to disclose

Introduction: Succinate dehydrogenase subunit germline variants are causative in hereditary pheochromocytoma-paraganglioma (PPGL) syndromes and may be associated with other tumors. Pathogenic variants (PVs) in the five succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD, and SDHAF2 are associated with gene-specific phenotypes. The full phenotype and penetrance of tumors in SDHA PVs are not well delineated.

Methods: A retrospective study was performed for two cohorts with SDHA PVs: 1) subjects with clinical genetic testing; and 2) subjects identified through whole exome sequencing (Regeneron Genetics) of an institutional biobank. SDHA-associated tumors were defined at PPGL, renal cell carcinomas (RCC), gastrointestinal stromal cell tumors (GIST), neuroblastomas, and pituitary adenomas, consistent with published guidelines. Clinical and genomic data was abstracted.

Results: Of 24 subjects with SDHA PVs diagnosed on clinical genetic testing, 14 were female (58%), and 19 were Caucasian (79%). Testing indications included 10 subjects with SDHx-associated tumors, 8 subjects undergoing familial cascade testing, and 6 subjects diagnosed on multi-gene panel testing for personal or family history of non-SDHA associated tumors. The most common PV was c.91C >T, p.R31X, in 11 subjects (46%). SDHA-associated tumors were found in 10 of 24 patients (42%). Of the 10 subjects screened for a personal history of SDHA-associated tumor, 7 had PPGL, 2 had RCC, and 1 had GIST. No SDHA-associated tumors were identified in patients undergoing cascade testing or multi-gene panel testing for non-SDHA associated tumors after full biochemical and imaging evaluation.

Conclusions: SDHA-associated tumors are rare in subjects with SDHA germline PVs. These data confirm the overall low penetrance of SDHA-associated tumors and support the new UK guidelines which suggest no role for tumor surveillance or cascade testing for SDHA in the absence of SDHA-associated tumors.

Learning Objectives:

List the tumors associated with succinate dehydrogenase A (SDHA) germline pathogenic variants.
Describe the rates of SDHA-associated tumors in patients undergoing cascade testing or multi-gene germline panel testing.
Understand the overall low penetrance of SDHA-associated tumors.