Submission Details

MCAT was first reported in relation to autosomal recessive optic atrophy 15 (MIM #620583) in 2020 (Li et al., PMID: 31915829). At least four variants (missense and frameshift) have been reported in two probands in two publications (PMID: 31915829, PMID: 33918393). One proband has a brother who shares the genotype and phenotype, but no other segregations are available from this family to enable scoring of co-segregation. Variants in MCAT have been reported in individuals with autosomal recessive optic atrophy 15 and one proband asserted to have combined oxidative phosphorylation deficiency. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found insufficient evidence of difference in molecular mechanism or inheritance pattern despite phenotypic variability of the probands. The combined oxidative phosphorylation deficiency case reported in Webb et. al 2023 is known to the group and was reviewed as a part of lumping and splitting (PMID:36881526). Although there is insufficient evidence to split the entities, the Webb case is not scored in this curation due to a lack of information about the ocular phenotype. Furthermore, the age of the proband at the time of the report and this curation is younger than the expected age of onset for the disease.

This gene-disease relationship is supported by functional alteration experimental evidence and a mouse model (PMID: 31915829). The effects of overexpression of the individual variant and variant pair in HEK293T cells was monitored through immunostaining and immunoelectron microscopy demonstrating that the mitochondria of cells transfected with either MCAT Leu81Arg and MCAT Leu81Arg/Arg212Trp were thinner than those of wild type MCAT cells. This showed that the expression of the mutants had a damaging effect on mitochondrial inner membrane morphology (PMID: 31915829). An MCAT floxed mouse (MCATt-Flox+/+, PMID: 23077570) was treated with adeno-associated virus 2 (AAV2)-Cre to knock out MCAT specifically in retinal ganglion cells. The results showed that depletion of MCAT expression in the mitochondria of the retinal ganglion cells disrupts maintenance of retinal ganglion cell axons, helping to explain a disruption in the relevant tissue observed in human probands (PMID: 31915829).

In summary, there is limited evidence to support the gene-disease relationship between MCAT and optic atrophy 15. Although more evidence from cases with MCAT variants will be needed to support a more definitive classification, no convincing evidence has yet emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on May 16th, 2024 (SOP Version 10).