FeedbackMassively Parallel Sequencing/ Multiplex Ligation-dependent Probe Amplification
Massively Parallel Sequencing
- Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
- To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor at 800-242-2787.
See Related Tests
Disease Overview
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are familial cancer syndromes characterized by benign or malignant neuroendocrine tumors: paragangliomas (neuroendocrine tumors of the autonomic nervous system) and pheochromocytomas (paragangliomas of the adrenal medulla). PGL/PCC tumors can affect both the sympathetic nervous system and the parasympathetic nervous system.
Clinical presentation varies but can include:
- Hypertension
- Paroxysmal tachycardia
- Heart palpitations
- Pallor/weight loss
- Hyperglycemia
- Metastatic disease
Pathogenic germline variants in SDHA, SDHB, SDHC, and SDHD, among other genes, predispose individuals to PGL/PCC tumors with an increased risk for malignancy. Whereas malignancy risk is low in tumors associated with pathogenic variants in the SDHA, SDHC, and SDHD genes, malignancy risk is high (34-97%) in tumors associated with variants in the SDHB gene.
Testing Strategy
Biochemical Testing
Often utilized in conjunction with computed tomography (CT) radiography, biochemical testing aids in characterizing the clinical and phenotypic features of PGL and PCC. Initial biochemical testing for hereditary PGL/PCC syndromes includes measurement of plasma-free metanephrines and/or urine metanephrines, dopamine (in plasma or urine), homovanillic acid, methoxytyramine, and fractionated catecholamines.
Pathogenic variants in the SDHA, SDHB, SDHC, and SDHD genes are associated with the following biochemical phenotypes :
- SDHA: mixed
- SDHB: norepinephrine/normetanephrine
- SDHC: norepinephrine/normetanephrine
- SDHD: norepinephrine/normetanephrine, often silent
Genetic Testing
Genetic testing should be considered in individuals who have PGL/PCC tumors or a relative with a hereditary PGL/PCC syndrome, and in individuals who meet any of the following criteria :
- Clinical evidence of a PGL/PCC syndrome
- Confirmed family history of PGL/PCC tumors
- Multiple, multifocal, or extra-adrenal tumors
- Malignancy associated with a PGL/PCC tumor
- Onset at <45 years of age
Offer targeted testing for a known familial variant. If no familial variant has been previously identified, order a multigene sequencing panel that includes deletion/duplication analysis.
For detailed information on the testing strategy for PGL/PCC tumors, refer to the ARUP Consult Pheochromocytoma - Paraganglioma topic.
Genetics
Genes Tested
| Gene Symbol | MIM # | Disorders | Inheritance |
|---|---|---|---|
|
SDHA |
600857 |
Paragangliomas 5 Neurodegeneration with ataxia and late-onset optic atrophy |
AD |
|
Dilated cardiomyopathy 1GG Mitochondrial complex II deficiency, nuclear type 1 |
AR |
||
|
SDHB |
185470 |
Paragangliomas 4 Gastrointestinal stromal tumor Pheochromocytoma Paraganglioma and gastric stromal sarcoma |
AD |
|
Mitochondrial complex II deficiency, nuclear type 4 |
AR |
||
|
SDHC |
602413 |
Paragangliomas 3 Paraganglioma and gastric stromal sarcoma Gastrointestinal stromal tumor |
AD |
|
SDHD |
602690 |
Paragangliomas 1, with or without deafness Paraganglioma and gastric stromal sarcoma Pheochromocytoma |
AD, with parent-of-origin effecta |
|
Mitochondrial complex II deficiency, nuclear type 3 |
AR |
||
|
aTumor predisposition generally occurs only when variants are inherited paternally. AD, autosomal dominant; AR, autosomal recessive |
|||
For information regarding other rare genes associated with hereditary PGL/PCC (eg, MAX, SDHAF2, or TMEM127), see the ARUP Consult Pheochromocytoma - Paraganglioma topic. See Related Tests for additional testing options.
Inheritance
- Primarily autosomal dominant
- Parent-of-origin effect for SDHD: tumor predisposition generally occurs only when variants are inherited paternally
- Rarely autosomal recessive (see Genes Tested for additional details)
Penetrance
Penetrance varies by gene and is incomplete and age dependent.
- SDHA: 10-50% by age 70
- SDHB: ~22-58% by age 60
- SDHC: 25% by age 60
- SDHD: ~43% by age 60
Test Interpretation
Sensitivity/Specificity
Clinical sensitivity: 22-45%
- Approximately 30% of individuals diagnosed with PGL/PCC have a detectable germline variant in one of the genes associated with PGL/PCC susceptibility.
Analytical Sensitivity
- For MLPA: >99%
- For massively parallel sequencing:
| Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
|
SNVs |
99.2 |
96.9-99.4 |
|
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
|
Deletions 11-44 bp |
99.9 |
87.8-100 |
|
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
|
Insertions 11-23 bp |
99.9 |
62.1-100 |
|
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Results
| Result As Reported in Chart | Variant(s) Detected | Clinical Significance |
|---|---|---|
|
Positive |
One pathogenic or likely pathogenic variant detected |
Confirms or predicts a diagnosis of a hereditary PGL/PCC syndromea |
|
See Note |
One variant of uncertain significance detected |
Unknown if variant is disease causing or benign |
|
Negative |
No pathogenic variants detected |
Diagnosis of hereditary PGL/PCC less likely, though not excluded |
|
aFor pathogenic and likely pathogenic SDHD variants, clinical manifestations generally only occur when inherited paternally. |
||
Limitations
- A negative result does not exclude a diagnosis of hereditary paraganglioma-pheochromocytoma.
- Diagnostic errors can occur due to rare sequence variations
- Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of targeted genes
- Regulatory region and deep intronic variants
- Noncoding transcripts
- The following exons are not sequenced due to technical limitations of the assay:
- SDHA (NM_004168) exon 14
- Breakpoints of large deletions/duplications
- Deletions/duplications in the SDHA gene
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Certain variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
References
-
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Preferred initial test when hereditary PGL/PCC is suspected