| A B C D E F G H I J K L M N O P Q R S T U V W X Y Z # |
Mayo #89550 Succinate Dehydrogenase (SDH)
Test Code89550
Alias/See Also
"SDH (Succinate Dehydrogenase) Gene
Pheocromocytoma
Paraganglioma
"
Pheocromocytoma
Paraganglioma
"
CPT Codes
81404-SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence 81405-SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary parganglioma-
Preferred Specimen
Whole Blood EDTA 3 mL
Minimum Volume
0.2 mL
Instructions
"Send specimen in original tube.
Additional Information: Transfusions will interfere with testing for up to 4 to 6 weeks. DNA obtained from white cells may not provide useful information for patients who received a recent transfusion of blood that was not leukocyte-reduced. Wait 4 to 6 weeks until transfused cells have left the patient's circulation before drawing the patient's blood specimen for genotype testing.
"
Additional Information: Transfusions will interfere with testing for up to 4 to 6 weeks. DNA obtained from white cells may not provide useful information for patients who received a recent transfusion of blood that was not leukocyte-reduced. Wait 4 to 6 weeks until transfused cells have left the patient's circulation before drawing the patient's blood specimen for genotype testing.
"
Transport Container
Lavender top (EDTA)
Specimen Stability
"Refrigerated (preferred)
Ambient
Frozen
"
Ambient
Frozen
"
Methodology
"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.) "
Setup Schedule
Monday 8 a.m
Report Available
"5-11 days Specimen Retention Time:
Whole blood 60 days DNA indefinitely, patient must request opt-out
"
Whole blood 60 days DNA indefinitely, patient must request opt-out
"
Reference Range
An interpretive report will be provided
Clinical Significance
Useful For Diagnosis of familial SDHB, SDHC, or SDHD gene mutations or deletions in patients with paragangliomas or pheochromocytomas
Used in conjunction with phenotyping to tailor optimal tumor-surveillance strategies
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).
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 usually do not 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 numbers 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 RCCs 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 and 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 truly 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 previously listed.
In order to minimize the cost of genetic testing, the clinical pattern of lesions in PGL and PC patients may 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.
Used in conjunction with phenotyping to tailor optimal tumor-surveillance strategies
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).
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 usually do not 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 numbers 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 RCCs 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 and 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 truly 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 previously listed.
In order to minimize the cost of genetic testing, the clinical pattern of lesions in PGL and PC patients may 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.
