Test Catalog

Test ID: SDHP    
SDHB, SDHC, SDHD Gene Panel, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Aiding in the diagnosis of hereditary paraganglioma-pheochromocytoma syndrome associated with SDHB, SDHC, and SDHD gene mutations

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

Testing includes full gene sequencing of the SDHB, SDHC, SDHD genes and multiplex ligation-dependent probe amplification for the detection of large deletions and duplications within the SDHB, SDHC, SDHD genes.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Succinate dehydrogenase (SDH) is a mitochondrial membrane-bound enzyme complex consisting of 4 subunits: SDHA, SDHB, SDHC, and SDHD. SDH is an oxidoreductase that catalyzes the oxidation of succinate to fumarate (tricarboxylic acid cycle function) and the reduction of ubiquinone to ubiquinol (respiratory chain function).


Heterozygous pathogenic variants of SDHB, SDHC, or SDHD result in an autosomal dominant tumor syndrome with variable lifetime penetrance. Patients have only 1 functioning germline copy of the affected SDH subunit gene. When the second, intact copy is somatically lost or mutated in target tissues, tumors develop. Tumorigenesis is believed to be mediated through the hypoxia-inducible factor (HIF) pathway, which gets activated as a consequence of the loss of function of the enzyme complex. Sympathetic and parasympathetic ganglia are preferentially affected, resulting in development of paragangliomas (PGLs) or pheochromocytomas (PCCs).

PGLs might include parasympathetic ganglia (neck and skull-base) or sympathetic ganglia (paravertebral sympathetic chain from neck to pelvis). PCCs can involve 1 or both adrenal glands. Almost all PCCs overproduce catecholamines, resulting in hypertension with a predilection for hypertensive crises. About 20% of PGL, mostly intra-abdominal, also secrete catecholamines. PGLs in the neck usually do not produce catecholamines. SDH-associated PGLs and PCCs are typically not malignant; however, malignancy has been described in a minority of patients (especially in patients with pathogenic SDHB variants). In addition, because of the germline presence of the pathogenic variant, new primary tumors might occur over time in the various target tissues.


SDHB is most strongly associated with PGL (usually functioning), but adrenal PCCs also occur, as do occasional gastrointestinal stromal tumors (GIST) and renal cell carcinomas (RCC). The lifetime penetrance of SDHB-related PGL/PCC is relatively low (25%-40%), but approximately half of the clinically affected patients will experience metastatic disease.


SDHD shows a disease spectrum similar to SDHB, except head and neck PGLs are more frequent than in SDHB, while functioning or malignant PGLs/PCCs and GISTs are less common. RCCs have thus far not been observed. The lifetime penetrance of paternally transmitted pathogenic SDHD variants is essentially 100%, while maternal transmission of a dysfunctional SDHD copy rarely leads to disease.


SDHC has, thus far, been mainly associated with PGLs of skull base and neck. Abdominal and functioning PGLs or PCCs are uncommon, and GISTs are very rare. RCCs have thus far not been observed. However, there is limited certainty about the SDHC genotype-phenotype correlations, as the reported case numbers are low. For the same reason there are no reliable estimates about the lifetime penetrance of SDHC-related PGL/PCC.


Collectively, heterozygous germline pathogenic variants of SDHB, SDHC, or SDHD are found in 30% to 50% of apparently sporadic PGL cases, and can be confirmed in approximately 90% of clinically hereditary cases. The corresponding figures are 1% to 25% and 20% to 30% for outwardly sporadic PCC and seemingly inherited PCC, respectively. The prevalence of pathogenic SDHB variants is higher than that of SDHD, which in turn exceeds the numbers for SDHC. SDHB and SDHC show classical autosomal dominant inheritance, while SDHD shows a modified autosomal dominant inheritance with chiefly paternal transmission, suggesting maternal imprinting, the exact molecular correlate of which remains unknown; however, recent evidence suggests tissue-specific distant imprinting that leads to long-range regulation of SDHD expression.


A minority of individuals with familial PGL will have pathogenic variants in other genes: SDHAF2 (also known as SDH5), TMEM127, and MAX.

Other genes have been described, but need additional study to confirm their clinical relevance and the utility of genetic testing: (i) SDHA variants have been described in familial PCC/PGL; however, all SDHA variants described thus far have been found in patients with seemingly sporadic PCC/PGL, not in familial cases, Moreover, the available data suggests that SDHA variants may have low penetrance and thus clinical utility of genetic testing is difficult to determine. (ii) EGLN1/PHD2, HIF2 alpha, IDH1, and KIF1 beta have also been proposed to predispose to PCC or PGL, but have thus far not been confirmed to do so, or, only do so very rarely.


Screening for pathogenic variants in SDH genes is not currently advocated for sporadic PCC, but is gaining in popularity, often alongside tests for mutations of other predisposing genes: SDHAF2, TMEM127, MAX, RET (multiple endocrine neoplasia type 2: MEN2), VHL (von Hippel-Lindau syndrome), NF1 (neurofibromatosis type 1). However, seemingly familial PCC cases that do not have an established diagnosis of a defined familial tumor syndrome, may benefit from SDH gene testing, along with screening of the other predisposing genes previously listed.


In order to minimize the cost of genetic testing, the clinical pattern of lesions in PGL and PCC patients may be used to determine the order in which the various predisposing genes listed above should be tested. The latest Endocrine Society Clinical Practice Guideline for pheochromocytoma and paraganglioma (2014) provides the current favored targeted testing approach. Genetic diagnosis of index cases allows targeted pre-symptomatic testing of relatives.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics recommendations as a guideline.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. 


Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Some individuals who have involvement of the SDHB, SDHC, or SDHD gene may have a pathogenic variant that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of SDH-related disease. For predictive testing of asymptomatic individuals, it is important to first document the presence of a pathogenic gene variant in an affected family member.


Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete. In some cases, DNA variants of undetermined significance may be identified. Rarely, sequence variants in primer- or probe-binding sites can result in false-negative test results (DNA sequencing) or either false-positive or false-negative results (multiplex ligation-dependent probe amplification: MLPA; deletion screening), due to selective allelic drop-out. False-negative or false-positive results can occur in MLPA deletion screening assays due to poor DNA quality. If results obtained do not match the clinical findings, additional testing should be considered.


In addition to disease-related probes, the MLPA technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.


Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common benign variants identified for this patient are available upon request.

Supportive Data

We sequenced the SDHB, SDHC, and SDHD genes in 42 specimens that had previously been tested for succinate dehydrogenase (SDH) variants at the National Institutes of Health (NIH). We were blinded to the original results until completion of all sequencing. All variants previously identified were confirmed. Overall, 27 patients had SDHB variants, 2 patients had SDHC variants, and 8 patients had SDHD variants. Inter- and intra-assay testing showed 100% concordance for all sequenced regions. Fifteen specimens from healthy individuals were also sequenced. All showed wild-type sequence for SDHB, SDHC, and SDHD.


Another 42 specimens from the NIH were tested for deletions of SDHB, SDHC, and SDHD, using multiplex ligation-dependent probe amplification-Luminex Flexmap technology. Seventeen specimens were found to have deleted portions of 1 of the SDH genes. These results were confirmed by the NIH. In addition, 50 specimens from healthy individuals were tested for deletions. We detected no deletions of SDHB, SDHC, or SDHD in any of these individuals.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-423

2. Briere JJ, Favier J, Gimenez-Roqueplo AP, Rustin P: Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation. Am J Physiol Cell Physiol 2006 Dec;291(6):C1114-1120

3. Young WF Jr: Paragangliomas: clinical overview. Ann NY Acad Sci 2006;1073:21-29

4. Bornstein SR, Gimenez-Roqueplo AP: Genetic testing in pheochromocytoma: increasing importance for clinical decision making. Ann NY Acad Sci 2006;1073:94-103

5. Benn DE, Richardson AL, Marsh DJ, Robinson BG: Genetic testing in pheochromocytoma and paraganglioma-associated syndromes. Ann NY Acad Sci 2006;1073:104-111

Special Instructions Library of PDFs including pertinent information and forms related to the test