YME1L1

Inheritance Pattern: Unknown

Disease ID:MONDO:0015011

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *YME1L1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 15, 2024. *YME1L1* encodes mitochondrial escape 1-like 1, an ATP dependent metalloprotease embedded in the inner mitochondrial membrane, that degrades intermembrane space and inner membrane proteins and modulates processing of OPA1, the inner mitochondrial membrane fusion protein. The first and only case report of *YME1L1*-related autosomal recessive primary mitochondrial disease was in 2016 (PMID: 27495975). While various names could be given to the constellation of features seen in those with *YME1L1*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *YME1L1* 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 one homozygous missense variant in one proband (four affected children in this consanguineous family) in one publication (PMID: 27495975). Clinical features in affected individuals include developmental delay, optic atrophy, hearing impairment, ataxia, and intellectual disability. Brain imaging was consistent with a leukoencephalopathy and brain atrophy. Lactate was elevated in blood and cerebrospinal fluid. Muscle biopsy showed parking lot and paracrystalline inclusions. Mitochondrial respiratory chain enzyme activities were normal in skin fibroblasts. The mechanism of disease is loss of function. This gene-disease association is also supported by the known biochemical function of YME1L1, functional alteration in patient and non-patient cells, and mouse and pig models (PMIDs: 27495975, 22262461, 26785494, 37123411). 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 July 15, 2024 (SOP Version 10).

Inheritance Pattern: AR

Disease ID:MONDO:0014753

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0015011

Submitter: ClinGen

The *YME1L1* gene was first reported in relation to optic atrophy in 2016, with the publication of four affected members of a consanguineous family harboring a homozygous missense variant (PMID: 27495975). All four affected family members received a diagnosis of optic atrophy and exhibited visual impairment, optic nerve hypoplasia, global developmental delay, expressive speech delay, and leukoencephalopathy. Substantial variability between the affected siblings was observed, and additional phenotypes observed in some but not all affected individuals included; macrocephaly, decreased body weight, elevated lactate, delayed CNS myelination, cerebellar hypoplasia, pigmentary retinopathy, congenital facial diplegia, splenomegaly, and constipation in infancy. A more detailed analysis of the proband revealed mitochondrial network fragmentation and altered mitochondrial cristae morphology with paracristalline inclusions in muscle biopsy, increased variability in muscle fiber diameter with grouped fibers indicating denervation, and fibroblast cells showing reduced mitochondrial mass despite normal levels of mitochondrial enzyme subunits and activities. Subsequent publications of additional probands have not yet emerged since this initial publication, although it is noteworthy that optic atrophy panels vary in their inclusion or exclusion of *YME1L1* at the time of this gene curation. This curation has scored one suspected disease-causing missense variant, which encodes an arginine to tryptophan substitution at position 149 and has been reported in one family in one publication (PMID: 27495975). Detection of the YME1L1 protein in the proband cells indicated reduced levels despite correct localization to the mitochondrial fraction, as well as partial inability to properly cleave substrate proteins such as PRELID1 and OPA1. Exogenous expression of the variant protein in mouse embryonic fibroblasts was unable to rescue the fragmentation of the mitochondrial network caused by *Yme1l1-/-* knockout (PMID: 27495975). The mechanism of pathogenicity may be partial loss-of-function, although this is difficult to determine conclusively from the limited amount of genetic evidence available. Co-segregation of the homozygous genotype with affected status in the proband’s family was also incorporated into the genetic evidence component of this curation (PMID: 27495975). This gene-disease association is also supported by biochemical evidence indicating that *YME1L1* encodes an AAA+ (ATPase Associated with diverse cellular Activities) protease that localizes to the mitochondrial inner membrane and controls protein homeostasis within the intermembrane space (PMID: 24176854). One of the other genes that encodes a mitochondrial protease, *AFG3L2*, similarly harbors variants that have been associated with optic atrophy 12 (PMID: 27786171). A proteomic screen for protein-protein interactions using key mitochondrial proteins as bait found that YME1L1 protein physically interacts with several other known mitochondrial proteins, including the OPA3 gene product (PMID: 27499296). Deletion of the *S. cerevisiae* ortholog *yme1* (yeast mitochondrial escape) results in DNA escape from mitochondria and migration to the nucleus, as well as fragmentation of the mitochondrial network, and functional mitochondrial abnormalities including a heat-sensitive respiratory-growth defect (PMID: 7803857, PMID: 8355690. PMID: 8514129). *Yme1l1* silencing or loss results in fragmentation of the mitochondrial network and other mitochondrial abnormalities in a variety of cell types (PMID: 24176854, PMID: 30544562) and model organisms ranging from murine to porcine (PMID: 26785494, PMID: 27495975, PMID: 30389680). While *Yme1l1* is essential for embryonic development in mice, tissue-specific *Yme1l1* loss in the nervous system results in locomotor defects (PMID: 30389680), similar to the results of *Yme1l1* silencing in *Drosophila* (PMID: 31125351). Tissue-specific knockout mice also show microphthalmia, cataracts, and retinal inflammation, consistent with mitochondrial dysfunction, although optic atrophy and ganglion cell phenotypes were not observed (PMID: 30389680). In summary, *YME1L1* has limited evidence of association with optic atrophy 11. The genetic evidence so far has been limited to a single family, while the experimental evidence is supportive of a role in mitochondrial function but not necessarily optic atrophy. Additional families will be required to reach a more definitive classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on January 16th, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0015011

Submitter: PanelApp Australia