Succinate Dehydrogenase (SDH) Gene, Deletion Detection
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 (PGL) or pheochromocytomas (PC). 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 (GIST: 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 and 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.
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
All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Rare, 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 is 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 or 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/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.
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.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008 Apr;10(4):294-300
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 Aug;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