SLC25A46

Inheritance Pattern: AR

Disease ID:MONDO:0014671

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014671

Submitter: ClinGen

SLC25A46 was first reported in 2015 associated to an autosomal recessive axonal sensorimotor polyneuropathy with a Charcot-Marie-Tooth phenotype combined with optic atrophy (HMSN6) and, to a variable extent, to further central nervous system manifestations including cerebellar ataxia and spasticity (Abrams et al., PMID: 26168012). The clinical pattern is heterogeneous. In contrast to optic atrophy, single cases have been reported without a detectable neuropathy at the date of examination (PMIDs: 32259769, 28369803). The age at onset varies from congenital to childhood manifestations. 12 missense, 2 nonsense, 2 frameshift, and 2 splice variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 20 probands in 11 separate publications (PMIDs: 26168012, 30178502, 27430653, 27543974, 28653766, 28558379, 28637197, 26951855, 27390132, 32259769, 28369803). This gene-disease relationship is supported by expression studies and animal models. SLC25A46 is a modified carrier protein localized in the outer mitochondrial membrane. It plays a major role in mitochondrial dynamics (fission) (Abrams et al., PMID: 26168012). In HeLa cells, SLC25A46 knockdown resulted in mitochondrial elongation, which was found to be associated to fission defects (electron microscopy, Abrams et al., PMID: 26168012). In a zebrafish model, motor neurons had significantly shorter axons tracts (Abrams et al., PMID: 26168012). In sciatic nerve of Slc25a46-/- mice, mitochondria clumped together with disorganized or abolished cristae (Li et al., PMID: 28934388), whereas AAV–Slc25a46 rescued the abnormal distribution of mitochondria in mice sciatic nerves accordingly improving nerve conduction studies as well (Li Yang et al., PMID:31943007). In summary, SLC25A46 is definitively associated with an autosomal recessive syndrome including axonal Charcot-Marie-Tooth disease, optic atrophy, and variable central nervous system manifestations. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0030260

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014671

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014671

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0016396

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0030260

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019551

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between SLC25A46 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 17, 2020. The SLC25A46 gene encodes a member of the SLC25 family of mitochondrial carrier proteins. The SLC25A46 protein is involved in mitochondrial dynamics, interacting with OPA1, MFN2, and mitochondrial contact site and cristae organizing system (MICOS) complex, and is likely important for lipid transfer from the endoplasmic reticulum to the mitochondrion, and for mitochondrial fission. Pathogenic variants in SLC25A46 have been associated with other phenotypes outside the Leigh syndrome spectrum including pontocerebellar hypoplasia, optic atrophy, and parkinsonism. The SLC25A46 gene has been reported in relation to autosomal recessive Leigh syndrome spectrum in a single publication in 2016 (PMID: 27390132). 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: 27390132). 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 data, functional alteration in patient cells, and model systems (PMIDs: 26168012, 25613900, 26951855, 28376086, 28934388, 28376083). In summary, there is limited evidence to support this gene-disease relationship. Although the total score (7) falls in the moderate range, only one case with Leigh syndrome spectrum has been reported, therefore this gene-disease association can only reach a limited classification at this time. 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 July 13, 2020 (SOP Version 7).