SDHD Gene Curation

Gene-disease assertions not curated here (add link or write note):

Disease	hereditary pheochromocytoma-paraganglioma
Inheritance	Autosomal dominant
Prevalence Possible sources Orphanet Medline Plus Genetics	1-9 / 1 000 000 Source: ORPHA:29072
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD	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 Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	Definitive Source: Hereditary Cancer GCEP, accessed 06.28.2023
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Loss of function Source: Hereditary Cancer GCEP, accessed 06.28.2023, described in evidence summary
Penetrance options Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID)	Reduced with age-related and parent of origin dependence. Paternal inheritance confers high risk. Sources: PMID: 20301715, 15064708, 26067997 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 options Congenital Pediatric Adolescent Adulthood Late adulthood (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 Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.	Moderate
Clinical Features	Multiple, multifocal, recurrent, early onset paraganglioma and/or pheochromocytoma and/or a family history. Paragangliomas that arise from neuroendocrine tissue, distributed from the skull base to the pelvic floor. Pheochromocytomas are paragangliomas that are confined to the adrenal medulla. They typically lead to catecholemine excess. Note: Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Symptoms of PGL/PCC result from effects of catecholamine hypersecretion (sustained or paroxysmal elvations in blood pressure, headach, episodic profuse sweating, forceful palpitations, pallor, and anxiety), palpable abdominal mass, enlarging mass of the skull base/neck, compromise of cranial nerves presenting as hoarseness, dysphagia, soft palate paresis, Horner syndrome; tinnitis. Sources: PMID: 20301715
Gene SOPs & Notes	SDHD has ≥7 pseudogenes and will require technical review and potentially orthogonal confirmation prior to reporting variants in this gene. https://www.ncbi.nlm.nih.gov/books/NBK535152/ Many extension variants in HGMD, use caution if looking for most 3' truncating variant.
Curation Summary: Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited	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). 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 CIT-130 - Getting issue details... STATUS

Disease	Mitochondrial complex II deficiency, nuclear type 3
Inheritance	Autosomal recessive
Prevalence Possible sources Orphanet Medline Plus Genetics	Source:
Rapid or full curation?	Rapid Full
ClinGen / GenCC / BabySeq / HGMD	ClinGen Mitochondrial diseases GCEP, Classified 04/04/2022, accessed 06.29.2023 - Limited GenCC - Mito complex II deficiency, MODERATE by Ambry
Clinical Validity Scoring Notes and points	ClinGen Mitochondrial diseases GCEP, Classified 04/04/2022, accessed 06.29.2023: The relationship between SDHD and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 4, 2022. The SDHD gene encodes the succinate dehydrogenase (SDH, mitochondrial respiratory chain complex II) subunit D, an integral membrane protein that anchors the SDH enzyme to the matrix side of the mitochondrial inner membrane. Defects of this protein lead to complex II deficiency. The* SDHD* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2014 (PMID: 24367056). While various names have been given to the constellation of features seen in those with autosomal recessive SDHD-related disease, pathogenic variants in this gene cause a primary mitochondrial disease when inherited in an autosomal recessive manner. Therefore, the SDHD 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:10683 ). Evidence supporting the relationship between SDHD and primary mitochondrial disease includes case-level data and experimental data. This curation included two missense variants and one start-loss variant in two cases from two publications (PMIDs: 24367056, 26008905). This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33162331). Mitochondrial dysfunction was recapitulated in a HEK293 knockout model (PMID: 34118887). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 4, 2022 (SOP Version 8). Updated internal lit review: PMID: 34012134, not included in the ClinGen curation. Reports the same missense variant scored in the above curation, c.205G>A p.Glu69Lys (0.002%, 2/113550 European chr in gAD), in a consanguineous Palistinian family. The variant is homozygous in affected individuals with features of mitochondrial disease including elevated serum lactate/ urinary Krebs cycle metabolites, nystagmus, optic atrophy, progressive microcephaly, generalised hypotonia, epileptic seizures, severe/profound intellectual disability/developmental impairment and cardiomyopathy. The variant segregates in two affected siblings, one unaffected sib wt/het, parents confirmed heterozygous. Variant was found via WES. Since variant was found via WES and there is segregation evidence in the family, will not deduct points for consanguinity. Segregation points = 0, variant points = 0.5 and as variant is homozygous scoring proband points = 1 NOTE: Invitae, Ambry, GeneDx, Rare disease group U. of Exeter all interpret this variant as P/LP for mitochondrial disease. Variation ID: 156153
Clinical Validity Points Total	5.5 + 1 = 6.5 Source: ClinGen Mitochondrial diseases GCEP, Classified 04/04/2022, accessed 06.29.2023
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed	LIMITED (Borderline Moderate, consider scoring any cases consistent with phenotype to bump up to Moderate) Source: ClinGen Mitochondrial diseases GCEP, Classified 04/04/2022, accessed 06.29.2023; PMID: 34012134
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other	Unknown
Penetrance options Complete (100%) High (≥90%) Reduced (<90% and >10%) Low (≤10%) (list source/PMID)	N/A Source:
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID)	N/A
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.	N/A
Clinical Features
Gene SOPs & Notes
Curation Summary: Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dsiease relationship is limited	SEE ABOVE (PGL-PCC)
Case ID, Curator name, Date, Jira ticket link	Andrea Oza 06.29.2023 CIT-130 - Getting issue details... STATUS

SDHD Gene Curation

hereditary pheochromocytoma-paraganglioma

Gene SOPs & Notes

Mitochondrial complex II deficiency, nuclear type 3