LIPE

Inheritance Pattern: AR

Disease ID:MONDO:0014431

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014431

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014431

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014431

Submitter: ClinGen

*LIPE* was first reported in relation to autosomal recessive familial partial lipodystrophy in 2014 (Albert et al., PMID 24848981) in 4 siblings homozygous for the variant NM_005357.4:c.3203_3221del (p.Val1068GlyfsTer102) (reported as c.2300_2318 [p.Val767Glyfs Ter102] to emphasize lack of translation of exon 1 in adipose tissue). We have curated the inheritance pattern for *LIPE*-related lipodystrophy as a recessive mode of inheritance as this has been consistently reported (Albert et al., PMID 24848981; Farhan et al., PMID: 25475467; Zotolov et al., PMID: 27862896; Sollier et al., PMID: 33112291; Zhou et al., PMID: 39113684). The phenotype is characterized by upper-body increased fat accumulation with lower-extremity lipoatrophy, together with hypertriglyceridemia, low high-density lipoprotein cholesterol, insulin resistance/diabetes, hepatic steatosis and myopathy and/or peripheral neuropathy (PMIDs: 24848981, 25475467, 27862896, 33112291, 39113684). Low serum adiponectin has been noted in two reports (PMIDs: 24848981, 33112291), and autofluorescent subretinal deposits have also been described (PMID: 33112291). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism or inheritance pattern or phenotypic variability. Therefore, the phenotypic presentations have been lumped into one disease entity, type 6 familial partial lipodystrophy (OMIM: 615980). Of note, p.V767GfsTer102/p.V1068GlyfsTer102 (see above) has been reported as enriched in an Amish cohort (~5% carrier frequency), and heterozygous carriers showed higher triglycerides, lower HDL-cholesterol, and increased diabetes/insulin resistance compared with controls (PMID 24848981); however, these heterozygous findings are nonspecific and were not curated as a distinct *LIPE*-haploinsufficiency disorder. Nine nonsense or frameshift variants that have been reported in 7 probands in 5 publications are included in this curation (PMIDs 24848981, 25475467, 27862896, 33112291, 39113684). The aggregated score for case-level is 21 points. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is supported by expression studies, functional alteration in patient-derived cells and mouse models (PMIDs: 15961788, 11316346, 10639158, 33112291, 24848981). Total points for experimental evidence are 9, but the experimental evidence score is limited to a maximum of 6 points. Total points for genetic and experimental evidence together are 18. In summary, there is definitive evidence supporting the relationship between *LIPE* and autosomal recessive type 6 familial partial lipodystrophy (OMIM:615980). 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 November 12, 2025 (SOP Version 11).