Lipodystrophy - childhood onset
Gene: PLIN1
As discussed with NHS endocrine specialist test group on 28.01.19, haploinsufficiency for this gene is NOT a cause of lipodystrophy, see PMID:30020498. As Robert Semple noted in 2015, all pathogenic mutations to date are frameshifts leading to translation of an aberrent C terminus of the protein ie. a dominant negative mechanism. Therefore, this gene is appropriate for inclusion on this panel, but only frameshift variants should be reported, as loss of function variants would not be expected to cause disease.Created: 5 Mar 2019, 1:06 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Lipodystrophy, familial partial, type 4
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Comment on list classification: This gene was downgraded from Green to Amber due to the findings of PMID: 30020498 - variants in this gene predicted to cause haplosufficiency are not a cause of familial partial lipodystrophy.Created: 20 Dec 2018, 5:46 p.m.
Comment on list classification: This gene was downgraded from Green to Amber due to the findings of PMID: 30020498 - variants in this gene predicted to cause haplosufficiency are not a cause of familial partial lipodystrophy.Created: 20 Dec 2018, 10:51 a.m.
PLIN1 haploinsufficiency is not responsible for the phenotype associated with this gene (PMID:30020498). It would appear that frameshifting variants that escape nonsense-mediated mRNA decay (NMD) are expressed and have a dominant negative effect. At least four frame shifting variants that result in the inclusion of aberrant C-terminal amino acids (125 - 166 amino acids) have been reported in cases of Lipodystrophy, familial partial, type 4 (OMIM:613877) (PMID:21345103;25114292;29747582), together with segregation information in two cases (PMID:21345103). Functional studies show that the variant mRNA is expressed at a lower level than wild type, the variant perilipin was correctly targeted to the lipid-droplet surface, but droplets were smaller than in the wild type cells (PMID:21345103; 25114292).Created: 21 Jan 2022, 11:10 a.m. | Last Modified: 21 Jan 2022, 11:10 a.m.
Panel Version: 2.18
Comment when marking as ready: Associated with phenotype in OMIM, not in G2P. At least three frame-shifting variants reported in five unrelated familiesCreated: 12 Aug 2016, 3:35 p.m.
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
All pathogenic mutations to date are frameshifts leading to translation of an aberrent C terminus of the proteinCreated: 12 Oct 2015, 8:43 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Familial Partial Lipodystrophy
Publications
Mode of pathogenicity
Other
Mode of pathogenicity for gene: PLIN1 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Publications for gene: PLIN1 were set to 21345103; 25114292; 30020498; 21757733
Publications for gene: PLIN1 were set to 21345103; 25114292; 30020498
Publications for gene: PLIN1 were set to 21345103; 25114292; 30020498
Gene: plin1 has been classified as Green List (High Evidence).
Robert Semple: All pathogenic mutations to da
Gene: plin1 has been classified as Amber List (Moderate Evidence).
Gene: plin1 has been classified as Amber List (Moderate Evidence).
Publications for gene: PLIN1 were set to 21345103; 25114292
gene: PLIN1 was added gene: PLIN1 was added to Lipodystrophy - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert Review Green Mode of inheritance for gene: PLIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLIN1 were set to 21345103; 25114292 Phenotypes for gene: PLIN1 were set to Lipodystrophy, familial partial, type 4, 613877