Succinate Dehydrogenase (SDH) Gene, Known Mutation
NY State Approved Indicates the status of NY State approval and if the test is orderable for NY State clients.
Diagnosis of suspected succinate dehydrogenase (SDH) disease, when familial mutations have been previously identified
Screening presymptomatic members of SDH families, when familial mutations have been previously identified
Tailoring optimal tumor-surveillance strategies for patients, when used in conjunction with phenotyping, when familial mutations have been previously identified
Profile Information A profile is a group of laboratory tests that are ordered and performed together under a single Mayo Test ID. Profile information lists the test performed, inclusive of the test fee, when a profile is ordered and includes reporting names and individual availability.
|Test ID||Reporting Name||Available Separately||Always Performed|
|SDHKS||SDH Known Mutation||No||Yes|
|SDHKQ||SDH Known Mutation Sequencing||No||Yes|
Testing Algorithm Delineates situation(s) when tests are added to the initial order. This includes reflex and additional tests.
Special Instructions and Forms Describes specimen collection and preparation information, test algorithms, and other information pertinent to test. Also includes pertinent information and consent forms to be used when requesting a particular test
Polymerase Chain Reaction (PCR) Amplification/DNA Sequencing and Deletion Detection by Multiplex Ligation-Dependent Probe Amplification (MLPA)
(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)
Reporting Name A shorter/abbreviated version of the Published Name for a test; an abbreviated test name
SDH Known Mutation
SDH (Succinate Dehydrogenase) Gene
Specimen Type Describes the specimen type needed for testing
Whole Blood EDTA
Specimen Required Defines the optimal specimen. This field describes the type of specimen required to perform the test and the preferred volume to complete testing. The volume allows automated processing, fastest throughput and, when indicated, repeat or reflex testing.
Container/Tube: Lavender top (EDTA)
Specimen Volume: 3 mL
Collection Instructions: Send specimen in original tube.
Additional Information: This test is only applicable if a mutation has previously been identified in a family member of this individual.
1. SDHB, SDHC, SDHD Gene Testing Patient Information Sheet (Supply T659) in Special Instructions.
2. 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 (Supply T576) is available in Special Instructions.
Specimen Minimum Volume Defines the amount of specimen required to perform an assay once, including instrument and container dead space. Submitting the minimum specimen volume makes it impossible to repeat the test or perform confirmatory or perform reflex testing. In some situations, a minimum specimen volume may result in a QNS (quantity not sufficient) result, requiring a second specimen to be collected.
Mild OK; Gross OK
Mild OK; Gross OK
Mild OK; Gross OK
Specimen Stability Information Provides a description of the temperatures required to transport a specimen to the laboratory. Alternate acceptable temperature(s) are also included.
|Whole Blood EDTA||Refrigerated (preferred)|
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).
Homozygous loss of function mutations or homozygous deletions of SDH subunit genes are embryonal lethal, with the exception of some biallelic SDHA mutations, which cause Leigh syndrome. No disease-associated heterozygote SDHA mutations or deletions have been reported. By contrast, heterozygous mutations and deletions of SDHB, SDHC, or SDHD result in a high life-time penetrance autosomal dominant tumor syndrome. 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. Sympathetic and parasympathetic ganglia are preferentially affected, resulting in development of paragangliomas (PGLs) or pheochromocytomas (PCs). PGLs might include parasympathetic ganglia (neck and skull-base) or sympathetic ganglia (paravertebral sympathetic chain from neck to pelvis). PCs can involve 1 or both adrenal glands. Almost all PCs 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 do not usually produce catecholamines. SDH-associated PGLs and PCs are typically benign; however, malignancy has been described in a minority of patients (especially in patients with SDHB mutations). In addition, because of the germline presence of the mutation or deletion, new primary tumors might occur over time in the various target tissues. Finally, tumors unrelated to chromaffin tissues, namely renal cell carcinoma (RCC: SDHB only) and gastrointestinal stromal tumors (GISTs: SDHB, SDHC, and SDHD), affect a minority of patients.
Collectively, heterozygous germline mutations and deletions of SDHB, SDHC, or SDHD are found in 30% to 50% of apparently sporadic PGL cases and can be confirmed in >90% of clinically hereditary cases. The corresponding figures are 1% to 10% and 20% to 30% for outwardly sporadic PC and seemingly inherited PC, respectively. The prevalence of SDHD mutations and deletions is higher than that of SDHB, which in turn exceeds the figures for SDHC. SDHB and SDHC mutations show classical autosomal dominant inheritance, while SDHD mutations show a modified autosomal dominant inheritance with chiefly paternal transmission, suggesting maternal imprinting (the molecular correlate of which remains unknown). SDHB is most strongly associated with PGL (usually functioning), but adrenal PCs also occur, as do occasional GISTs and RCCs, with the latter being found exclusively in this subtype. SDHD shows a disease spectrum similar to SDHB, except head and neck PGLs are more frequent than in SDHB, while functioning or malignant PGLs/PCs and GISTs are less common. SDHC has thus far been mainly associated with PGLs of skull base and neck. Abdominal/functioning PGLs or PCs are uncommonly seen in patients with SDHC mutations, and GISTs are very rare. However, there is limited certainty about the SDHC genotype-phenotype correlations, as the reported case numbers are low.
Genetic testing for SDHB, SDHC, and SDHD germline mutations and deletions is highly accurate in identifying affected patients and presymptomatic individuals. It is advocated in all patients that present with PGL. Accurate diagnosis assists in designing optimal follow-up strategies, since the rate of new or recurrent tumors is much higher in patients with SDH mutations or deletions than in true sporadic cases.
Screening for mutations in SDH genes is not currently advocated for sporadic adrenal PC, but is gaining in popularity, often alongside tests for mutations of other predisposing genes: RET (multiple endocrine neoplasia type 2, MEN2), VHL (von Hippel-Lindau syndrome), and NF1 (neurofibromatosis type 1). Seemingly familial PC cases, who do not have an established diagnosis of a defined familial tumor syndrome, should be screened for SDH gene mutations, along with screening of the other predisposing genes listed above.
In order to minimize the cost of genetic testing, the clinical pattern of lesions in PGL and PC patients might be used to determine the order in which the 3 disease-associated SDH genes are tested. Genetic diagnosis of index cases allows targeted presymptomatic 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.
The presence of a known disease-causing mutation or deletion confirms the diagnosis of succinate dehydrogenase (SDH)-associated paraganglioma (PGL) or pheochromocytoma (PC).
The presence of DNA sequence variations or deletions that have not been previously linked to PGL or PC is classified as a sequence variation of unknown significance. Within this group, the observed variants are classified as:
-Likely to be disease-causing: this includes all DNA sequence variations that are predicted to result in a nonfunctioning protein. Examples include premature stop-codons, small indels causing frameshifts, mutated start codons, changes that definitively alter splice sites, and large deletions affecting > or =1 exon.
-Possibly disease-causing: this includes all DNA sequence variations for which it is uncertain whether they will or will not result in a protein with impaired function. Examples include previously unreported missense mutations, in-frame exonic small indels, and intronic mutations or small indels that have some potential of affecting splicing. For this category of sequence changes we will usually provide some additional guidance in an expanded interpretive report.
-Unlikely to be disease-causing: this includes all sequence variations of the gene that will probably not result in any changes to the translated protein. Examples include silent mutations (no amino acid change), intronic variants that are not predicted to affect splicing, sequence changes that are seen in conjunction with another, known disease-causing changes (SDH mutations are autosomal dominant), and sequence changes that have been seen many times during routine testing in both affected and unaffected patients.
Many mutations have been correlated with certain phenotypes, as indicated in the "Clinical Information" section. When such correlations are known for a detected mutation or deletion, they are included in the report.
The detection of a disease-causing mutation, deletion, insertion, or a large deletion, indicates that SDH gene inactivation has occurred. In a tumor, such inactivation is usually biallelic.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Rarely, unknown polymorphisms 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.
The current test does not examine the promoters, other gene regulatory elements, or most of the intronic portions of the SDHB, SDHC, and SDHD genes. The impact of this on detection rates is unknown. Based on observations in other genetic disorders, it is generally believed that <5% of disease-causing mutations occur in these regions.
There may be (several) other, as yet unidentified, genes that can cause a phenotypically similar picture as succinate dehydrogenase (SDH) mutations and deletions.
Collectively, the above causes, along with various other preanalytical and analytical problems that are not unique to genetic testing (eg, specimen mix-up), probably account for the estimated false-negative rate of <10% (likely <5%) that is observed with genetic SDH testing.
The absence of any sequence variations and deletions within SDHB, SDHC, and SDHD, as compared to the wild-type reference sequence, or the presence of only known normal variant sequence polymorphisms, excludes SDH-associated paraganglioma (PGL) or pheochromocytoma (PC) with at least 90% certainty.
When testing for known mutations in family members of index cases, the presence or absence of the known mutation predicts with near 100% certainty, whether the tested person has inherited SDH-associated PGL or PC.
If the specimen is from a tumor (frozen tissue), in particular a sporadic tumor (rather than a SDH-related tumor), 1 of the alleles might be inactivated by promoter hypermethylation. Our assay does not detect hypermethylation.
This test does not reliably detect deletions in formalin-fixed, paraffin-embedded tissues.
We sequenced the SDHB, SDHC, and SDHD genes in 42 specimens that had previously been tested for succinate dehydrogenase (SDH) mutations at the National Institutes of Health (NIH). We were blinded to the original results until completion of all sequencing. All previously found mutations were confirmed. Overall, 27 patients had SDHB mutations, 2 patients had SDHC mutations, and 8 patients had SDHD mutations. 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 Provides recommendations for further in-depth reading of a clinical nature
1. Briere JJP, 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
2. Young WF Jr: Paragangliomas: Clinical Overview. Ann NY Acad Sci 2006 Aug;1073:21-29
3. Bornstein SR, Gimenez-Roqueplo AP: Genetic Testing in Pheochromocytoma: Increasing Importance for Clinical Decision Making. Ann NY Acad Sci 2006;1073:94-103
4. Benn DE, Richardson AL, Marsh DJ, Robinson BG: Genetic Testing in Pheochromocytoma and Paraganglioma-Associated Syndromes. Ann NY Acad Sci 2006;1073:104-111
Method Description Describes how the test is performed and provides a method-specific reference
SDHB, SDHC, and SDHD gene sequences are generated by PCR amplification of all 18 exons, including flanking intronic sequence, followed by automated fluorescent-dye terminator DNA sequencing. Detection of large deletions involving SDHB, SDHC, and SDHD, or parts of these genes, is accomplished by multiplex ligation-dependent probe amplification and detection on Luminex beads specific to each exon. (Unpublished Mayo method)
Day(s) and Time(s) Test Performed Outlines the days and times the test is performed. This field reflects the day and time the sample must be in the testing laboratory to begin the testing process and includes any specimen preparation and processing time required before the test is performed. Some tests are listed as continuously performed, which means assays are performed several times during the day.
Monday through Friday; Varies
Analytic Time Defines the amount of time it takes the laboratory to setup and perform the test. This is defined in number of days. The shortest interval of time expressed is "same day/1 day," which means the results may be available the same day that the sample is received in the testing laboratory. One day means results are available 1 day after the sample is received in the laboratory.
Maximum Laboratory Time Defines the maximum time from specimen receipt at Mayo Medical Laboratories until the release of the test result
Specimen Retention Time Outlines the length of time after testing that a specimen is kept in the laboratory before it is discarded
Whole blood 60 days DNA indefinitely, patient must request opt-out
Performing Laboratory Location The location of the laboratory that performs the test
Test Classification Provides information regarding the medical device classification for laboratory test kits and reagents. Tests may be classified as cleared or approved by the US Food and Drug Administration (FDA) and used per manufacturer's instructions, or as products that do not undergo full FDA review and approval, and are then labeled as an Analyte Specific Reagent (ASR), Investigation Use Only (IUO) product, or a Research Use Only (RUO) product.
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 Provides guidance in determining the appropriate Current Procedural Terminology (CPT) code(s) information for each test or profile. The listed CPT codes reflect Mayo Medical Laboratories interpretation of CPT coding requirements. It is the responsibility of each laboratory to determine correct CPT codes to use for billing.
81403-Known familial variant, not otherwise specified, for gene listed in Tier 1 or Tier 2, DNA sequence analysis
LOINC® Code Information Provides guidance in determining the Logical Observation Identifiers Names and Codes (LOINC) values for the result codes returned for this test or profile.
|Result ID||Reporting Name||LOINC Code|
|SDHKQ||SDH Known Mutation Sequencing||In Process|
|57089||Reason for Referral||42349-1|