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Disease

Mitochondrial complex II deficiency, nuclear type 3

Inheritance

Autosomal recessive

Prevalence

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titlePossible 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

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titleClassifications (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

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titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown

Penetrance

Expand
titleoptions

Complete (100%)

High (≥90%)

Reduced  (<90% and >10%)

Low (≤10%)

(list source/PMID)

N/A

Source:

Age of Onset

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titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

N/A

Severity

Expand
titleOptions

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

Sources:

Gene SOPs & Notes

Curation Summary:

Expand
titleExamples

- 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 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

Jira Legacy
serverSystem JIRA
serverIdeee25142-2510-336f-918a-865682ebdf2e
keyCIT-130

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