MICOS13

Inheritance Pattern: AR

Disease ID:MONDO:0009787

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MICOS13* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 7, 2023. The *MICOS13* gene encodes a subunit of the mitochondrial contact site and cristae junction organizing system (MICOS) protein complex. The MICOS13 protein is needed for maintenance of crista junctions, cristae morphology and inner membrane architecture, and formation of contact sites to the outer mitochondrial membrane. Of note, the *MICOS13* gene has previously been referred to as *QIL*1 or *C19ORF70*. The *MICOS13* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2016 (PMIDs: 27485409, 27623147) in individuals with early-onset encephalopathy and liver disease. While various names have been given to the constellation of features seen in those with *MICOS13*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MICOS13* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique homozygous variants (two frameshift, two splice) reported in four unrelated individuals in four publications (PMIDs: 27485409, 27623147, 32749073, 29618761). Variants co-segregated with disease in two additional family members in two families. Additional cases are available in the literature, but the maximum for genetic evidence has been reached. Affected individuals typically present in the infantile or early childhood period and features seen in affected individuals include small for gestational age, intrauterine growth restriction, microcephaly, seizures, neurologic deterioration, failure to thrive, liver disease, sensorineural hearing loss, optic atrophy, lactic acidosis, 3-methylglutaconic aciduria, and cerebellar and vermis atrophy. Skeletal muscle, fibroblasts, and/or liver showed decreased activities of mitochondrial respiratory chain complexes I, III, and IV. The mechanism of disease appears to be loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease; evidence of mitochondrial dysfunction and impaired MICOS complex assembly following knockdown in non-patient cells; rescue of MICOS complex assembly and mitochondrial function via expression of wild-type in patient cells; and recapitulation of mitochondrial morphology defects observed in patient tissue in a Drosophila muscle- and neuron-specific knockdown model (PMIDs: 33340416, 27623147, 32749073, 25997101). In summary, there is definitive evidence to support the relationship between *MICOS13* and autosomal recessive primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 7, 2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: Illumina