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Disease | Mitochondrial complex II deficiency, nuclear type 3 | ||||||||
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Inheritance | Autosomal recessive | ||||||||
Prevalence
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Source: | ||||||||
Rapid or full curation? |
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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
| 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
| Unknown | ||||||||
Penetrance
(list source/PMID) | N/A Source: | ||||||||
Age of Onset
(list source/PMID) | N/A | ||||||||
Severity
| N/A | ||||||||
Clinical Features | Sources: | ||||||||
Gene SOPs & Notes | |||||||||
Curation Summary:
| The SDHD gene has 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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