CMD1GG; FP; PGL5; SDH1; SDH2; SDHF
The SDHA gene is associated with autosomal dominant hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndromes (MedGen UID: 481622), gastrointestinal stromal tumors (GIST) (PMID: 21505157, 22974104, 23060355), and autosomal recessive mitochondrial complex II deficiency with or without cardiomyopathy (MedGen UID: 344401).
Order this gene as a single gene test.
SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.
Invitae tests that include this gene:
The SDHA gene is a tumor suppressor that encodes a flavoprotein, one of the four nuclear-encoded peptide subunits in complex II. Complex II, also known as succinate dehydrogenase or succinate-ubiquinone oxidoreductase, is a complex of the mitochondrial respiratory chain.
SDHA: hereditary paraganglioma pheochromocytoma
MedGen UIDs: 481622
Single pathogenic variants in the SDHA gene are associated with the development of paragangliomas (PGL) and pheochromocytomas (PCC) as seen in hereditary paraganglioma-pheochromocytoma syndrome, gastrointestinal stromal tumors (GIST), and Carney-Stratakis syndrome (PMID: 21505157, 22974104, 23060355, 23512077, 20484225). It is unclear if pathogenic variants in SDHA are associated with other cancers as the data are limited and emerging (PMID: 23633203, 26259135). The clinical presentation is highly variable among those with a pathogenic variant in SDHA and may be difficult to predict. An individual with a single SDHA 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 (called head-and-neck paragangliomas, or HNP) to the pelvis. PGLs located outside the head and neck most commonly occur in the adrenal glands and are called pheochromocytomas (PCCs) (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 SDHA, that can result in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 24903423, 24893135, 20301715, 23512077, 20484225).
Pathogenic variants in SDHA are primarily associated with a risk of developing PCC, but sympathetic non-adrenal PGL of abdomen and thorax as well as HNP have been reported (PMID: 24096523, 26113606). The age at diagnosis is highly variable (PMID: 24899893) and the risk of malignancy appears to be low (PMID: 20301715, 21752896). Additionally, the penetrance appears to be low, meaning most individuals with a pathogenic variant in this gene will not develop PGL (PMID: 26113606).
Gastrointestinal stromal tumors (GIST) are rare, typically adult-onset sarcomas that may be either benign or malignant. They can occur sporadically or due to a heritable pathogenic variant in a susceptibility gene, such as SDHA. GIST can develop anywhere along the GI tract, which includes the esophagus, stomach, gallbladder, liver, small intestine, colon, rectum, anus, and lining of the gut. GISTs arise from a specific cell type, interstitial cells of Cajal (ICC), which line the walls of the GI tract. More than half of GISTs start in the stomach. The next-largest proportion of cases start in the small intestine, followed by the omentum and peritoneum (National Library of Medicine. Genetics Home Reference. Gastrointestinal stromal tumor. Accessed June 2015). GISTs may develop in individuals with pathogenic variants in SDHA, with a significant proportion identified among pediatric patients (PMID: 21505157, 22974104, 23060355, 27011036).
Carney-Stratakis syndrome (CSS) is an autosomal dominant condition that can be caused by pathogenic variants in SDHA (PMID: 25741136). This rare disorder is characterized by the development of PGL, GIST, or both (PMID: 23036227, 24899893, 24903423, 20301715, 25741136). CSS is very similar to but distinctly different from Carney triad, a typically sporadic condition associated with pulmonary chondromas, GIST, and PGL (PMID: 20119652, 26173966).
SDHA also has preliminary evidence for an association with renal cancer, and is therefore available as a “preliminary-evidence” gene on Invitae’s Renal/Urinary Tract Cancer panel (PMID: 26722403, 25034258). Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary-evidence genes.
SDHA is a tumor-suppressor gene involved in complex II of the mitochondrial electron transport chain (UniProtKB – P31040 (SDHA_HUMAN); http://www.uniprot.org/uniprot/P31040. Accessed September 2015; PMID: 20484225). The succinate dehydrogenase enzyme, which is part of complex II, is composed of four subunit proteins encoded by SDHA, SDHB, SDHC, and SDHD. These are nuclear genes whose transcripts are then imported into the mitochondria, where they are modified, folded, and assembled (PMID: 21771581). Lack of any component of mitochondrial complex Ⅱ will result in instability of the entire complex (PMID: 25741136). 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.
Pathogenic variants SDHA resulting in GIST, PGL, and/or PCC have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it). An individual with a variant in SDHA has a 50% risk of passing that variant on to offspring.
Individuals with a pathogenic variant in SDHA are also carriers of mitochondrial complex II deficiency syndrome. This autosomal recessive condition is characterized by neurodegeneration and encephalomyopathy (PMID: 22972948, MedGen UID: 344401). For there to be a risk of this condition in offspring, both parents each have to have a pathogenic variant in SDHA; in such a case, the risk of having an affected child is 25%.
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: 21771581). There is currently no clear consensus regarding a screening and surveillance protocol for individuals with pathogenic SDHA variants; however, lifelong annual biochemical and clinical surveillance has been suggested (PMID: 24893135, 20301715, 24523625, 25385035):
|Age to begin screening (years)||5–10 years|
|Physical exam and blood pressure||Every 6–12 months|
|Urinary excretion of fractionated metanephrines and catecholamines in 24 hours||Annually|
|Full body MRI||Every 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 important to note that individuals with a pathogenic SDHA variant may be at a greater risk of developing PGL or PCC when living in higher altitudes or when chronically exposed to hypoxic conditions. In general, inactivating mutations in one of the succinate dehydrogenase genes, which includes SDHA, can lead to accumulation of succinate, the formation of reactive oxygen species, and the activation of hypoxia-dependent pathways (PMID: 24899893). 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, therefore 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 SDHA 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 SDHA 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
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|
*SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.