MFN2

Inheritance Pattern: AD

Disease ID:MONDO:0007908

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012231

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:1060153

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019551

Submitter: Orphanet

Inheritance Pattern: SD

Disease ID:MONDO:0015358

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014906

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0019549

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0011002

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:1060153

Submitter: ClinGen

*MFN2* was first reported in relation to autosomal recessive multiple symmetric lipomatosis with partial lipodystrophy (OMIM: 151800) in 2008 (Nicholson et al., PMID 18458227) in a single individual who was homozygous for the p.Arg707Trp variant. We have curated the inheritance pattern for *MFN2*-related lipodystrophy as a recessive mode of inheritance as this has been consistently reported since 2008 (Carr et al., PMID 26114802; Sawyer et al., PMID 26085578; Capel et al., PMID: 30158064; Rocha et al., PMID: 28414270). One specific *MFN2* variant, p.Arg707Trp, has been reported in all multiple symmetric lipomatosis with partial lipodystrophy cases to date. The majority of individuals are homozygous for this variant, although the p.Arg707Trp has also been reported in trans with a second *MFN2* variant in several cases, including a multi-exon deletion, an in-frame deletion, and a splice site variant (Carr et al., PMID 26114802; Rocha et al., PMID: 28414270; Braszak-Cymerman et al., PMID: 37162328). Individuals typically present with upper body adipose overgrowth and lipodystrophy in the arms and legs, and most individuals also develop progressive distal weakness and axonal neuropathy. Of note, the severity of lipomatosis is variable (Capel et al., PMID: 30158064). Individuals also develop, hypertriglyceridemia, and hepatic steatosis over time (Sawyer et al., PMID 26085578; Capel et al., PMID: 30158064; Rocha et al., PMID: 28414270) with glucose intolerance progressing over time. Another feature is very low circulating leptin levels and low adiponectin levels (Capel et al., PMID: 30158064; Rocha et al., PMID: 28414270). Less common features include hearing loss, and precocious puberty (Capel et al., PMID: 30158064, Nicholson et al., PMID 18458227). At least four multiple symmetric lipomatosis with partial lipodystrophy-causing *MFN2* variants have been reported; however, all affected individuals have at least one copy of the p.Arg707Trp allele. Evidence supporting the association of this gene with lipodystrophy includes case-level data, and experimental data. The aggregated score for case-level data is 12 points. Variants in this gene were curated for this summary in 15 probands in 6 publications (PMIDs: 18458227, 26114802, 26085578, 37162328, 28414270, 30158064). More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached; this has not been curated exhaustively. This gene-disease relationship is supported by functional assays, knock-in mouse models, expression studies, and protein interactions (PMIDs: 26085578, 36722855, 28414270). Total points for experimental evidence are 3.5. Total points for genetic and experimental evidence together are 15.5. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern, mutational mechanism, and phenotype for variants causing lipomatosis and lipodystrophy vs. those causing neuromuscular conditions. Therefore, we curated *MFN2* for autosomal recessive multiple symmetric lipomatosis with partial lipodystrophy (OMIM: 151800) and semidominant axonal hereditary motor and sensory neuropathy will be curated separately in split curations. Of note, heterozygous family members of individuals with *MFN2*-related autosomal recessive multiple symmetric lipomatosis with partial lipodystrophy with mild Charcot Marie Tooth phenotypes have been reported, although unaffected heterozygous carriers have also been described though the extent of detailed phenotyping in those cases is unclear (Capel et al., PMID: 30158064; Sawyer et al., PMID 26085578; Braathen et al., PMID: 20350294). In summary, *MFN2* is definitively associated with autosomal recessive multiple symmetric lipomatosis with partial lipodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes GCEP on September 10, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0012231

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014906

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: SD

Disease ID:MONDO:0012231

Submitter: ClinGen

MFN2 encodes for GTPases on the outer mitochondrial membranes. The gene was first described as the cause of CMT2 in 14 families in 2004 (PMID: 15064763). A subsequent study screened 323 CMT2 patients and identified significant variants in 29 of them; up to 33% of patients with family history of CMT carried a likely pathogenic MFN2 variant (PMID: 16714318). Chung et al reported 10 pathogenic mutations in 26 patients from 15 families (PMID: 16835246). MFN2 is expressed in the liver and adipose tissues, and is abundantly expressed in the brain. MFN2 is essential for mitochondrial fusion and contact, mitochondrial transport, ER-mitochondrial contact, and is a mediator of cellular autophagy and mitophagy. Two studies have reported semidominant families with axonal motor and sensory neuropathy with pathogenic variants in MFN2 identified through candidate gene sequencing. Phenotype was variable in many studies, even with the same mutation, as some families had optic atrophy, but others did not. Optic atrophy as an additional symptom to CMT2 was first reported in 6 families by Zuchner et al, where three probands carried de novo MFN2 changes (PMID: 16437557). Other phenotypes reported included periventricular and subcortical hyperintense lesions by brain MRI in eight patients, sensorineural hearing loss in three patients, and bilateral extensor plantar responses in two patients. The role of MFN2 with mitochondrial function, shape, mobility and fusion has been supported with experimental functional studies (Baloh et al, 2007, PMID: 17215403; Chen et al, 2003, PMID: 12527753). In summary, MFN2 is DEFINITIVELY associated with semidominant axonal hereditary motor and sensory neuropathy due to the presence of both genetic case level evidence and experimental evidence.