COX4I1

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *COX4I1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 18, 2024. The *COX4I1* gene encodes an isoform of a subunit of cytochrome *c* oxidase (COX) that is more ubiquitously expressed than its other isoform *COX4I2*. *COX4I1* was first reported in relation to autosomal recessive primary mitochondrial disease in 2017 (PMID: 28766551) in a child from consanguineous parents with short stature, failure to thrive, normal development, and chromosome breakage studies overlapping with Fanconi anemia. Given the functional studies performed in this report (including COX deficiency on respiratory chain analysis with complementation studies), this Expert Panel elected to include this report in this current curation but noted that the Fanconi anemia phenotype is not typical of primary mitochondrial disorders. While various names have been given to the constellation of features seen in those with *COX4I1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *COX4I1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *COX4I1* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on December 16, 2020 (SOP V7), with a final classification of Limited. This current curation for the association with primary mitochondrial disease includes the single case included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This included two homozygous variants, one missense, and one indel with functional evidence of mitochondrial dysfunction (c.303_304delinsTT; p.Lys101_Thr102delinsAsnSer). In addition to the case with Fanconi anemia, there is a case report of an infant with Leigh syndrome spectrum disorder (PMID: 31290619). The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of COX4I1 as a subunit of complex IV, as well as functional alteration in non-patient cells (PMIDs: 33672589, 33578848, 32075102). This curation fell between Limited and Moderate. This Gene Curation Expert Panel (GCEP) elected to classify this gene-disease association as Limited given that the two reported cases are markedly different, and because the Fanconi anemia phenotype is not typical of primary mitochondrial disease leaving the possibility open that there is a separate genetic etiology in the first reported proband. No convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease GCEP on March 18, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between COX4I1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 16, 2020. The COX4I1 gene encodes cytochrome c oxidase (complex IV) subunit 4I1. Defects of this protein lead to complex IV deficiency. The COX4I1 gene has been reported only once in relation to autosomal recessive Leigh syndrome spectrum, in 2019 (PMID: 31290619), and this has been the only case reported to date. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous variant identified in one case in one publication (PMID: 31290619). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, and animal models (PMIDs: 28593021, 18853439, 31127358). 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on December 16, 2020 (SOP Version 7).

Inheritance Pattern: AR

Disease ID:MONDO:0033651

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009068

Submitter: Orphanet