CBT1; CII-4; CWS3; PGL; PGL1; QPs3; SDH4; cybS
The SDHD gene is associated with autosomal dominant hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndromes (MedGen UID: 358258) and gastrointestinal stromal tumors (GIST) (PMID: 24886695).
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The SDHD gene is a tumor suppressor that encodes an integral membrane protein, 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.
SDHD: hereditary paraganglioma pheochromocytoma
MedGen UIDs: 376098, 18419
Single pathogenic variants in the SDHD gene are associated with the development of paragangliomas (PGL) and pheochromocytomas (PCC) as seen in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 24903423, 24899893, 24893135, 20301715, 23512077), gastrointestinal stromal tumors (GIST) (PMID: 25741136), and Carney-Stratakis syndrome (PMID: 23036227, 24899893, 24903423, 20301715, 25741136, 17667967). It has been suggested that variants in SDHD are associated with an increased risk of other cancers such as pituitary adenoma (PMID: 26113606, “(external) 24096523”:http://www.ncbi.nlm.nih.gov/pubmed/24096523); however, the data are currently limited and emerging. The clinical presentation is highly variable among those with a pathogenic variant in SDHD and may be difficult to predict. An individual with a SDHD pathogenic variant will not necessarily develop cancer in their lifetime, but the risk for cancer is increased over that of the general population.
Paragangliomas (PGL) 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 the head and neck most commonly occur in the adrenal glands and are called pheochromocytomas (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 SDHD, that can result in hereditary paraganglioma-pheochromocytoma syndrome (PMID: 24903423, 24893135, 20301715, 23512077).
Individuals with a pathogenic variant in SDHD are primarily at risk to develop multiple benign parasympathetic HNPs, but multiple extra-adrenal sympathetic and adrenal tumors are also frequent (PMID: 24899893, 15328326). Approximately 68%-79% of affected individuals develop HNPs (PMID: 16317055, 15328326, 24899893, 19802898), 39% develop thoracic/abdominal PGL, and 29%–53% develop PCC (PMID: 24899893, 15328326, 16317055, 19802898). Compared to sporadic tumors, those with hereditary pathogenic variants in SDHD tend to present at younger ages and are more likely to have multiple synchronous neoplasms and multifocal, bilateral, recurrent disease (PMID: 24899893, 24893135). The mean age of tumor presentation is approximately 23–30 years (PMID: 24899893, 23072324). Malignant transformation of PGLs has rarely been associated with the SDHD gene (PMID: 24899893, 26113606).
GISTS 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 SDHD (PMID: 25741136). 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 (PMID: 26113606, 17193819, 25741136, National Library of Medicine. Genetics Home Reference. Gastrointestinal stromal tumor. Accessed June 2015 https://ghr.nlm.nih.gov/condition/gastrointestinal-stromal-tumor).
Carney-Stratakis syndrome (CSS) is an autosomal dominant condition that can be caused by pathogenic variants in SDHD. This rare condition is characterized by the development of PGL, GIST, or both (PMID: 23036227, 24899893, 24903423, 20301715, 25741136, 17667967). 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).
There is also preliminary evidence for an association between SDHD and breast cancer (PMID: 21979946, 25694510), thyroid cancer (PMID: 19802898, 25694510, 15328326), and renal cell carcinoma (PMID: 15328326, 23083876). Therefore, this gene is available as a “preliminary evidence” gene on Invitae’s Breast Cancer Panel, Breast and Gyn Cancers Panel, Thyroid Cancer Panel, and Renal/Urinary Tract Cancers Panel. 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.
SDHD is a tumor-suppressor gene that is involved in complex II of the mitochondrial electron transport chain (UniProtKB – 014521 (DHSD_HUMAN); http://www.uniprot.org/uniprot/O14521 Accessed September 2015). 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 the instability of the entire complex (PMID: 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 SDHD gene follows traditional Mendelian autosomal dominant inheritance, there seems to be demonstration of parent-of-origin effects. SDHD generally causes disease when the pathogenic variant is inherited from the father (PMID: 20301715, 15264276) whereas the risk of clinical disease after maternal transmission appears to be low (PMID: 26113606, 25300370, 21937622). The offspring of an individual with a pathogenic SDHD variant, regardless of parental origin, has a 50% risk of passing the variant on to offspring. The underlying cause of this parent-of-origin is poorly understood (PMID: 26113606, 26067997). 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 has been suggested to 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 SDHD variants, lifelong annual biochemical and clinical surveillance is suggested (PMID: 24893135, 20301715, 24523625, 25385035):
|Age to begin screening (years)||5 years–10 years|
|Physical exam and blood pressure||Every 6–12 months|
|Urinary excretion of fractionated metanephrines and catecholamines in 24 hours||Annually|
|MRI/CT of skull base and neck||Every 6-36 months|
|MRI/CT of abdominal, thorax, and pelvis||Every 1-4 years|
|Periodic MRI or CT and 123I-MIBG (metaiodobenzylguanidine) scintigraphy||Every 1–4 years|
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 SDHD 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 SDHD, leads 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, 24523625).
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 SDHD 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 SDHD 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: February 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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|