Associated disorders

The SDHAF2 gene is associated with autosomal dominant hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes (MedGen UID: 313270).

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The SDHAF2 gene is a regulatory subunit that encodes a mitochondrial protein involved with the flavination of a succinate dehydrogenase complex subunit. Also, SDHAF2 is necessary for SDH activity.

SDHAF2: hereditary paraganglioma pheochromocytoma
MedGen UID: 357076

Clinical condition
Single pathogenic variants in the SDHAF2 gene are associated with the development of the paragangliomas (PGL) and pheochromocytomas (PCC) seen in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 20071235, 22241717). It is unclear if pathogenic SDHAF2 variants are associated with other cancers as the data are currently limited and emerging. The clinical presentation is highly variable and may be difficult to predict. An individual with a SDHAF2 pathogenic variant will not necessarily develop cancer in their lifetime, but the risk for cancer is increased over that of the general population.

PGLs are rare, adult-onset, typically benign neuroendocrine tumors that arise from paraganglia. Paraganglia are a collection of neuroendocrine tissues that are distributed throughout the body, from the middle ear and skull base to the pelvis. PGLs that develop in the head and neck are called head-and-neck paragangliomas (HNP). PGLs located outside of the head and neck most commonly occur in the adrenal glands and are called PCC (also known as chromaffin tumors). PCCs are catecholamine-secreting PGLs that are confined to the adrenal medulla, as defined by the The World Health Organization Tumor Classification; however, this term may also be used to refer to catecholamine-producing PGLs regardless of whether they are adrenal or extra-adrenal (PMID: 24899893). These lesions can cause excessive production of adrenal hormones, resulting in hypertension, headaches, tachycardia, anxiety, and sweaty or clammy skin in some individuals (PMID: 21771581, 24893135, 20301715). Most cases of PGL and PCC are sporadic, but approximately one-third are familial and due to an identifiable pathogenic variant in a susceptibility gene, such as SDHAF2, that can result in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 24903423, 24893135, 20301715).

Current literature suggests that pathogenic variants in SDHAF2 are associated with a predisposition to develop one or more HNPs, with an average age of onset of 33 years (range: 22–47 years) (PMID: 20301715, 24523625, 25385035). SDHAF2 pathogenic variants are very rare, appear to be highly penetrant, and are associated with a low risk of malignancy (PMID: 24899893, 20301715, 24523625, 26347711).

Gene information
SDHAF2 is a tumor-suppressor gene that encodes succinate dehydrogenase assembly factor 2. SDHAF2 is a nuclear gene that plays an important role in the activation of the succinate dehydrogenase enzyme, as part of complex II of the mitochondrial electron transport chain (PMID: 20301715, 17193819, 19628817, UniProtKB – Q9NX18. Accessed September 2015). The succinate dehydrogenase enzyme is composed of four subunit proteins encoded by the SDHA, SDHB, SDHC, and SDHD genes. These are nuclear genes whose transcripts are then imported into the mitochondria, where they are modified, folded, and assembled (PMID: 21771581). SDHAF2 is responsible for post-translational modification of SDHA, which enables SDH complex activity (PMID: 24903423, 25741136, 26347711). Lack of any component of mitochondrial complex Ⅱ will result in the instability of the entire complex (PMID: 25741136, 17967865). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers may be increased.

While the SDHAF2 gene follows traditional Mendelian autosomal dominant inheritance, there appears to be demonstration of parent-of-origin effects. Current literature suggests that SDHAF2 generally causes disease when the pathogenic variant is inherited from the father (PMID: 20301715) whereas the risk of clinical disease after maternal transmission seems to be very low. The underlying cause of this parent-of-origin effect has yet to be elucidated (PMID: 26113606, 26067997). The offspring of an individual with a pathogenic SDHAF2 variant, regardless of parental origin, has a 50% risk of passing the variant on to offspring. It is now possible to identify at-risk relatives who can pursue testing for this specific familial variant.

It is suggested that individuals with hereditary paraganglioma-pheochromocytoma syndrome, along with their at-risk relatives, have regular clinical monitoring by a physician or medical team with expertise in the treatment of hereditary GIST and PGL/PCC syndromes. A consultation with an endocrine surgeon, endocrinologist, and otolaryngologist is also recommended to establish an individualized care plan (PMID: 20301715).

Screening should begin between five and ten years of age, or at least ten years before the earliest age at diagnosis in the family (PMID: 24903423, 20301715, 24523625). Although there is currently no clear consensus regarding a screening and surveillance protocol for individuals with pathogenic SDHAF2 variants, lifelong annual biochemical and clinical surveillance has been suggested (PMID: 20301715, 24893135, 24523625, 25385035):

  • Physical exam and blood pressure at the time of diagnosis and then every 6-12 months
  • 24-hour urinary excretion of fractionated metanephrines and catecholamines and/or plasma fractionated metanephrines at least annually to detect metastatic disease, tumor recurrence, or development of additional tumors
    • Follow up with imaging by CT, MRI, 123I-MIBG (metaiodobenzylguanidine) scintigraphy, or FDG-PET if the fractionated metanephrine and/or catecholamine levels become elevated, or if the original tumor had minimal or no catecholamine/fractionated metanephrine excess
  • Periodic MRI or CT inclusive of head, neck, thorax, abdomen, and pelvic areas
    • In order to minimize radiation exposure, MRI may be the preferable imaging modality with CT and nuclear imaging reserved to further characterize detected tumors
    • Imaging modalities should be at the discretion of the managing provider due to conflicting data regarding the utility and efficacy of the various options (PMID: 25385035)
  • Evaluation of cases with extra-adrenal sympathetic PGL and PCC for blood pressure elevations, tachycardia, and other signs and symptoms of catecholamine hypersecretion
  • Medical genetics consultation

Summary of Medical Management and Surveillance Recommendations (PMID: 24893135, 20301715, 25385035):

RecommendationSDHAF2 Screening
Age to begin screening5 years–10 years
Physical exam and blood pressureEvery 6–12 months
Urinary excretion of fractionated metanephrines and catecholamines in 24 hoursAnnually
Whole body MRIEvery 2–3 years (PMID: 25385035)

It remains unclear whether imaging studies should be conducted as frequently in childhood as in adulthood (PMID: 24523625).

It is is important to note that individuals with a pathogenic SDHAF2 variant may be at a greater risk of developing PGL or PCC when living in higher altitudes or when chronically exposed to hypoxic conditions. Avoidance of living at high altitudes and activities that promote long-term exposure to hypoxia and predispose to chronic lung disease (e.g., smoking) is therefore encouraged (PMID: 20301715).

Syndromes associated with a predisposition to PGLs and PCCs may be associated with high morbidity and significant complications, which can lead to decreased lifespan and quality of life. As a result, early screening and therapeutic interventions are imperative. However, the natural history of hereditary paraganglioma-pheochromocytoma syndrome is variable and continues to evolve. This can often result in significant uncertainty regarding long-term prognosis. Targeted genetic counseling may help patients cope with this diagnosis while keeping them an active participant in the management of their condition (PMID: 24854530). In addition, the clinical manifestations of PGLs and PCCs are broad; many symptoms can mimic minor ailments such as headaches and palpitations. Once a pathogenic variant has been identified, patients should be encouraged to have a low threshold for contacting their healthcare provider for further evaluation of unusual symptoms (PMID: 24854530).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant in SDHAF2 is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding SDHAF2 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow condition-specific screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review Date: January 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
SDHAF2 NM_017841.2