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Disease | hereditary pheochromocytoma-paraganglioma | ||||||||
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Inheritance | Autosomal dominant (with paternal transmission effect) | ||||||||
Prevalence
| 1-9 / 1 000 000 Source: ORPHA:29072 | ||||||||
Rapid or full curation? |
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Hereditary Cancer GCEP, accessed 06.28.2023 | |||||||||
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 and pheochromocytomas tumors within multiple organ systems 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, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, this is a lumping Curation for SDHD and SDHD associated Hereditary Paraganglioma-Pheochromocytoma syndromes (PGL/PCC) including autosomal dominant inherited Paraganglioma 1 with or without deafness (MIM: 168000) and Pheochromocytoma (MIM: 171300). The autosomal recessive inherited Mitochondrial Complex II Deficiency (MIM: 252011) will be curated separately. SDHD encodes one of the subunits of SDH (succinate dehydrogenase), a component of complex II in mitochondria. It was the first tumor suppressor gene identified as encoding a mitochondrial protein. SDHD was first reported in relation to PGL/PCC in 2000 [Baysal et al., PMID: 10657297]. Two missense variants and seven nonsense variants from two large studies [PMID: 16317055 and 12000816] are included in this curation. Maternal transmission has been rarely reported and Dutch founder variants are recorded [PMIDs: 19584903, 11391798 and PMID: 15010701]. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Experimental evidence showed absent or decreased expression of SDHB, the iron protein, catalytic component of mitochondrial complex II [PMIDs: 19576851, 20236688 and 14595761], and absent or decreased SDH enzyme activity [PMIDs 14595761 and 15652751] in human SDHD related tumors. There was no mouse model available as homozygous sdhd KO mice are embryonically lethal and heterozygous mice do not develop any tumors [PMIDs: 19956719, 15572694]. Biochemical studies on accumulated succinate due to reduced SDH activity and succinated induced pseudo-hypoxic drive, i.e., stabilization of HIF1a, inhibition of HIF prolyl hydroxylases are repetitively reported [PMIDs: 26971832, 17102089, 15987702]; in addition, SDHD related up-regulation of the p21WAF1/Cip1 in liver and kidney of the conditional tamoxifen-inducible SDHD-ESR mutant mice and two immortalized SDHD-ESR cell lines are also reported. The p21 is implicated in many biological processes including cell cycle, survival, and cancer [PMID: 24465590]. A truncated hSDHD mutant, W105X (previously W66X), expressed in immortalized Chinese hamster lung fibroblast model showed increased genomic instability mediated by increased ROS [PMID: 22041456]. In summary, the SDHD gene is definitely associated with autosomal dominant HPGL/PCC syndrome. This has been repeatedly demonstrated in both the genetic, and experimental, biochemical and functional studies, and has been upheld over time. Source: Hereditary Cancer GCEP, accessed 06.28.2023 | ||||||||
Clinical Validity Points Total | 17 Source: Hereditary Cancer GCEP, accessed 06.28.2023 | ||||||||
Clinical Validity Classification
| Definitive Source: Hereditary Cancer GCEP, accessed 06.28.2023 | ||||||||
Molecular Mechanism
| Loss of function Source: Hereditary Cancer GCEP, accessed 06.28.2023, described in evidence summary | ||||||||
Penetrance
(list source/PMID) | Reduced with age-related and parent of origin dependence. Paternal inheritance confers high risk. Sources: PMID: 20301715, 15064708, 26067997, 27856506 and ClinGen actionability https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC150 , note that it is age related and by age 80 penetrance of any outcome is reported to be 100%. | ||||||||
Age of Onset
(list source/PMID) | Adolescence-Adulthood Source: 14-47 years for SDHD per ClinGen clinical actionability https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC150 | ||||||||
Severity
| Moderate | ||||||||
Clinical Features |
Gastrointestinal stromal tumors (GISTs) may also be observed. Sources: PMID: 20301715 | ||||||||
Gene SOPs & Notes |
Many extension variants in HGMD, use caution if looking for most 3' truncating variant. | ||||||||
Curation Summary:
| The SDHD gene is associated with autosomal dominant hereditary pheochromocytoma-paraganglioma, which is characterized by multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma (PMID: 20301715). Penetrance is age-related and parent-of-origin dependent, with increased penetrance in individuals with a paternally-inherited variant (PMID: 15064708, 26067997, 27856506). Variants in this gene have also been reported in individuals with mitochondrial complex II deficiency, (PMID: 24367056, 26008905, 33162331, 34118887, 34012134); however, evidence supporting this gene-disease relationship is limited. | ||||||||
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 06.29.2023
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