SDHB Gene Curation
- Andrea Oza
Gene-disease assertions not curated here (add link or write note):
Disease | Hereditary pheochromocytoma-paraganglioma |
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Inheritance | Autosomal dominant |
Prevalence | 1-9 / 1 000 000 Source: ORPHA:29072
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Rapid or full curation? | Rapid Full |
ClinGen Hereditary Cancer, accessed 07.07.2023 | |
Clinical Validity Scoring Notes and points | Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL/PCC) [MONDO:0017366, PMID: 20301715] are associated with an increased risk of multiple paragangliomas, pheochromocytomas and gastrointestinal stromal tumors (GIST) including malignant PCC/PGLs transmitted in autosomal dominant inheritance. The molecular mechanism is loss of function in one of the 4 genes comprising the succinate dehydrogenase and SDHAF gene for flavination of SDHA, as well as stabilization of the SDH complex. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, for SDHB, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability for tumor risk. Therefore, this is a lumping curation for SDHB and SDHB associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 4 (MIM: 115310), Gastrointestinal stromal tumor (MIM: 606764) and Pheochromocytoma (MIM: 171300). SDHB encodes the iron sulfur protein, one of the five subunits of SDH (succinate dehydrogenase), a component of complex II in mitochondria. SDHB was first reported in relation to PGL/PCC in 2001 [Astuti et al., PMID: 11404820]. Pathogenic variants in SDHB including frameshift, nonsense, missense (e.g. p.Pro197Arg, p.Val140Phe and p.Arg242His), splice site and large (exon) deletion variants were reported in the literature with incomplete penetrance and variable expressivity [PIMDs: 19389109, 19802898 and 25827221]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. There is extensive experiment evidence including reduced or absent SDHB protein expression [PMID:19576851], reduced enzyme activity [PMID:22835832], increased succinate level, the hallmark of tumorigenesis in PGL and PCC, and increased nuclear expression of HIF1α (hypoxia inducible factor 1α) [PMID:15987702] in tumor cells of patients who carry germline SDHB variants. However, the knockout mouse homolog of human SDHB is homozygous-lethal [PMID 27626380]. In summary, the SDHB gene is definitely associated with autosomal dominant HPGL/PCC syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Source: ClinGen Hereditary Cancer, accessed 07.07.2023 |
Clinical Validity Points Total | 18 Source: ClinGen Hereditary Cancer, accessed 07.07.2023 |
Clinical Validity Classification Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive Source: ClinGen Hereditary Cancer, accessed 07.07.2023 |
Molecular Mechanism Loss of function Gain of function Dominant negative Unknown Other | Loss of function Source: ClinGen Hereditary Cancer, accessed 07.07.2023. PMIDs: 19576851, 22835832, 19802898)
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Penetrance Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID) | Reduced |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Adolescence to adulthood |
Severity | Moderate |
Clinical Features |
Sources: PMID: 20301715 |
Gene SOPs & Notes | LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant |
Curation Summary: | The SDHB gene is associated with autosomal dominant hereditary pheochromocytoma-paraganglioma, which is characterized by multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma (PMID: 20301715). It has also been associated with autosomal recessive mitochondrial disease, which is characterized by hypotonia, leukoencephalopathy, developmental regression, and complex II deficiency on muscle biopsy (PMID: 22972948, 26642834). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, 07.07.2023 https://broadinstitute.atlassian.net/browse/CIT-130 |
Disease | Mitochondrial disease |
|---|---|
Inheritance | Autosomal recessive |
Prevalence | Unknown (rare) Source:
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Rapid or full curation? | Rapid Full |
ClinGen Mitochondrial Disease GCEP, accessed 07.07.2023 | |
Clinical Validity Scoring Notes and points | The relationship between SDHB and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The SDHB gene encodes the succinate dehydrogenase complex iron sulphur subunit B. Defects of this protein lead to complex II deficiency. The SDHB gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2012 (PMID: 22972948). While various names have been given to the constellation of features seen in those with autosomal recessive SDHB-related disease, pathogenic variants in this gene cause a primary mitochondrial disease when inherited in an autosomal recessive manner. Therefore, the SDHB phenotype has been split, with one disease entity being autosomal recessive primary mitochondrial disease, according to the ClinGen Lumping and Splitting Framework. Of note, this gene has also been implicated in autosomal dominant hereditary pheochromocytoma-paraganglioma. This gene disease relationship has been assessed separately (https://search.clinicalgenome.org/kb/genes/HGNC:10681 ). Evidence supporting the relationship between SDHB and primary mitochondrial disease includes case-level data and experimental data. This curation included five missense variants in eight cases from five reports (PMIDs: 22972948, 26925370, 26642834, 27604842, 32124427). Of note, the c.143A>T (p.Asp48Val) was associated with disease in six probands, including four cases in a homozygous state and two cases in a compound heterozygous state. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33162331). Mitochondrial dysfunction and developmental alterations associated with PMD were recapitulated in knockout animal models including round worm (Caenorhabditis elegans), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio) (PMIDs: 32859697, 17056719, 33156815). In summary, there is definitive evidence to support the relationship between SDHB and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on March 7, 2022 (SOP Version 8). Source: ClinGen Mitochondrial Disease GCEP, accessed 07.07.2023 |
Clinical Validity Points Total | 18 Source: ClinGen Mitochondrial Disease GCEP, accessed 07.07.2023 |
Clinical Validity Classification | Definitive Source: ClinGen Mitochondrial Disease GCEP, accessed 07.07.2023 |
Molecular Mechanism | Unknown All case evidence from mitochondrial disease GCEP are missense. HGMD - Missense variants and a stop-loss (p.*160Leu). No other LOF variants associated with mito disease. Source:
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Penetrance (list source/PMID) | Reduced? Source: 26925370 (may be a non-segregation) |
Age of Onset (list source/PMID) | Congenital to early childhood Source: 26642834 |
Severity | Severe |
Clinical Features | Hypotonia, leukoenceophalopathy, developmental regression, spasticity, abnormal brain MRI, Elevated brain succinate via MR spectroscopy. Labs: Abnormal muscle biopsy - severe deficiency in SDH activity via histochemical analysis. Severe and isolated deficiency involving complex II. Normal metabolic profile including plasma, very long chain fatty acids, carnitine profile, amino acids, ammonia and lactate. Normal urinary organic and amino acids, glycosaminoglycans, oligosaccarides, cerebrospinal fluid glucose and lactate. Sources: PMID: 22972948, 26642834 |
Gene SOPs & Notes |
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Curation Summary: | The SDHB gene is associated with autosomal dominant hereditary pheochromocytoma-paraganglioma, which is characterized by multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma (PMID: 20301715). It has also been associated with autosomal recessive mitochondrial disease, which is characterized by hypotonia, leukoencephalopathy, developmental regression, and complex II deficiency on muscle biopsy (PMID: 22972948, 26642834). |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza, 07.07.2023 https://broadinstitute.atlassian.net/browse/CIT-130 |