Sign in →

Test ID: SDHP SDHB, SDHC, SDHD Gene Panel

Useful For

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

Method Name

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis and Gene Dosage Analysis by Multiplex Ligation-Dependent Probe Amplification (MLPA)

Reporting Name

SDHB, SDHC, SDHD Gene Panel

Specimen Type

Varies


Shipping Instructions


Specimen preferred to arrive within 96 hours of draw.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.


Specimen Minimum Volume

1 mL

Specimen Stability Information

Specimen Type Temperature Time
Varies Ambient (preferred)
  Frozen 
  Refrigerated 

Clinical Information

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

An interpretive report will be provided.

Interpretation

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.

Clinical Reference

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

Day(s) and Time(s) Performed

Performed weekly, varies

Analytic Time

14 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81403 x 2

81404 x 2

81405 x 2

LOINC Code Information

Result ID Test Result Name Result LOINC Value
37460 Result Summary 50397-9
37461 Result No LOINC Needed
37462 Interpretation 69047-9
37463 Additional Information 48767-8
37464 Specimen 31208-2
37465 Source 31208-2
37466 Released By No LOINC Needed

Forms

1. SDHB, SDHC, SDHD Gene Testing Patient Information (T659) in Special Instructions is required.

2. Informed Consent for Genetic Testing (T576) in Special Instructions is required.

3. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.

4. If not ordering electronically, complete, print, and send an Oncology Test Request Form (T729) with the specimen (http://www.mayomedicallaboratories.com/it-mmfiles/oncology-request-form.pdf)

Mayo Medical Laboratories | Genetics and Pharmacogenomics Catalog Additional Information:

mml-inherited-molecular