Submission Details

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).