Lipodystrophy - childhood onset

Gene: PLIN1

Green List (high evidence)

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

• 30020498

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.

Green List (high evidence)

Green List (high evidence)

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 families

Created: 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

Green List (high evidence)

All pathogenic mutations to date are frameshifts leading to translation of an aberrent C terminus of the protein

Created: 12 Oct 2015, 8:43 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Familial Partial Lipodystrophy

Publications

• PMID: 21345103

Mode of pathogenicity
Other