Submission Details

Human pathogenic LMNA variants were first reported in association with autosomal dominant lipodystrophy in 1974 (Dunnigan et al, PMID 4362786). We have curated the inheritance pattern for LMNA related lipodystrophy as semidominant because, while most cases are autosomal dominant, a recessive mode of inheritance has been reported very rarely (Soyaltin et al, PMID:32685188, Savage et al, PMID:15298354, Le Dour et al, PMID:21346069).

Both partial and complete loss of LMNA function due to heterozygous and homozygous or compound heterozygous variants in the LMNA have been reported. Typical autosomal dominant cases due to heterozygous variants present in exon 8 and 11 of LMNA with partial loss of subcutaneous limb and gluteal fat, insulin resistance, diabetes, hypertension and hypertriglyceridemia (Morel et al, PMID:16636128, Akinci et al, PMID:28641778). The occasional recessive cases due to homozygous or compound heterozygous variants are usually present with severe lipodystrophic syndrome with diabetes and /or acanthosis nigricans, liver steatosis, hypertriglyceridemia, lower serum leptin and adiponectin levels, and dilated cardiomyopathy with conduction disturbances (Le Dour et al, PMID:21346069, André et al PMID: 25819867, Treiber et al PMID: 34292171).

At least 200 lipodystrophy - causing LMNA variants (primarily missense than frameshift or nonsense) have been reported in humans. Evidence supporting the association of this gene with lipodystrophy includes case level data, segregation data, and experimental data. The aggregated score for case-level and segregation data is 12 points. Of the over 200 reported, variants in this gene have been curated for this summary in 13 probands in 10 publications (PMIDs: 32686188,19201734, 18041775, 15298354, 16636128, 30177912, 28641778, 32524016, 21346069, 29108996) with 8 cases presenting as familial partial lipodystrophy and 5 cases with congenital generalized lipodystrophy. 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, expression studies and functional alterations (Corsa CAS, et al, PMID:34088712, Friesen M et al, PMID:29108996, Fagerberg L et al, PMID:243099898, Wojtanik et al, PMID:19201734). Total points for the experimental evidence are 5.5. Total points for genetic and experimental evidence together are 17.5.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we observed both differences in inheritance pattern and phenotypic variability, but also overlap in the implicated variants. Specifically, LMNA has two associated lipodystrophy diseases entities, namely the more commonly associated autosomal dominant familial partial lipodystrophy (OMIM:151660), and the more rarely associated autosomal recessive congenital, generalized lipodystrophy. Because the latter is rare and there is overlap in the implicated variants, these two entities have been lumped in a single curation of lipodystrophy (MONDO: 0006573). In addition, LMNA has several other associated diseases, including but not limited to: dilated cardiomyopathy (MONDO: 0005021), arrhythmogenic right ventricular cardiomyopathy (ARVC; MONDO: 0016587), Charcot-Marie-Tooth disease (MIM: 5005588), Emery-Dreifuss muscular dystrophy (MIM: 181350 and 616516), and Hutchinson-Gilford progeria (MIM: 176670). While there is some genetic and phenotypic overlap, there is enough distinction among these phenotypes and their implicated variants that these entities have (dilated cardiomyopathy and ARVC) or will be curated separately.

In summary, LMNA is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.