IDH3B

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012943

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0800393

Submitter: ClinGen

Patients with disease-causing variants in the *IDH3B* gene were first reported in 2008 and showed retinal degeneration with late-onset (between 30-50 years of age, Hartong et al., 2008). This discovery was made through the evaluation of microarray results from 7 families with retinal disease patients and the identification of 2 novel loss-of-function variants. In these two families with homozygous variants in *IDH3B*, patients exhibited non-syndromic retinal degeneration and none of them showed other symptoms of mitochondrial dysfunction (neurological, neuromuscular etc) (Hartong et al., 2008). Cases caused by variants in the *IDH3B* gene are diagnosed with retinitis pigmentosa 46 (MIM#612572), an autosomal recessive form of Inherited retinal diseases (IRD) characterized by night blindness, loss of peripheral vision, and reduced visual acuity. Dysfunction of IDH3B has been previously correlated with retinal degeneration and male infertility in humans, but tissue-specific effects of IDH3 dysfunction are unclear. To account for a spectrum of retinal phenotypes that may be caused by variants in this gene, and in accordance with the ClinGen Lumping and Splitting guidelines, the disease entity used for this curation is *IDH3B*-related retinopathy (MONDO:0800393). A total of 4 *IDH3B* variants have already been identified underlying retinitis pigmentosa. The mutation spectrum in *IDH3B* includes 2 missense and 2 frameshift variants (PMID: 18806796, 31736247, 30718709). Case-level evidence is not sufficient to draw any specific conclusions on phenotype/genotype correlations in a yet limited number of patients. In this curation, data from 2 consanguineous families and 2 isolated individuals with 4 unique variants (frameshift, missense), were collected from 3 publications (Hartong et al., 2008, PMID: 18806796, Zenteno, J. C., et al., 2019, PMID: 31736247, Jespersgaard, C., et al., 2019, PMID: 30718709). *IDH3B* encodes the 385-amino-acid β subunit of isocitrate dehydrogenase 3 (IDH3), a key enzyme in the mitochondrial tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle). IDH3 catalyzes the decarboxylation of isocitrate into α-ketoglutarate and concurrently converts NAD+ into NADH, which feeds into oxidative phosphorylation to generate ATP. IDH3 is a heterotetramer composed of the αβ and αγ heterodimers. The α subunit is critical for catalytic activity, but it requires the β and γ subunits for structural assembly and allosteric regulation. Without the β or γ subunit, the α subunit alone has almost no activity. Like the *IDH3A* and *IDH3G* genes encoding other subunits, *IDH3B* expresses abundantly in mitochondria-rich tissues such as the heart, skeletal muscle, and brain. Another mitochondrial enzyme, nicotinamide adenine dinucleotide phosphate (NADP)-IDH (IDH2), also converts isocitrate to α-ketoglutarate but uses the cofactor NADP+ instead of NAD+. NADP-IDH may actually be the principal catalyst of the isocitrate to α-ketoglutarate reaction in the citric acid cycle in all tissues, and IDH3 serves as an accessory enzyme that augments or regulates the reaction, with the retina being particularly sensitive to the loss of this accessory activity (Hartong et al., 2008). As human patients with apparent loss-of-function variants in *IDH3B* seem to present only with retinal degeneration, Findlay et al., 2018 produced a CRISPR/Cas9-induced mutation in the mouse *Idh3b* gene. *Idh3b−/−* mutant mice are fully viable and show no signs of retinal degeneration within 6 months of age. Although histology and ERG analysis show no significant loss of retinal structure or function, the *Idh3b* mouse retina was confirmed to exhibit a TCA cycle defect. Since the human patients with clear null mutations in IDH3B develop RP in adulthood; the mutant mice might not live long enough to develop retinal degeneration, or this might simply reflect species differences (Findlay et al., 2018). In summary, *IDH3B* is moderately associated with *IDH3B*-related retinopathy. This has been demonstrated over time in both the research and clinical diagnostic settings. A Moderate classification has been reached due to the need for further evidence at both the genetic and experimental levels, and additional studies will be required to reach a more definitive classification. This finding was approved by the ClinGen Retina Gene Curation Expert Panel on December 1st, 2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0012943

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012943

Submitter: PanelApp Australia