PLIN1 Haploinsufficiency Is Not Associated With Lipodystrophy

Area of Science:

• Genetics
• Endocrinology
• Metabolic Diseases

Background:

• Monogenic partial lipodystrophy is a rare genetic disorder with varied causative mechanisms.
• Previous reports linked specific heterozygous protein-extending frameshift variants in PLIN1 to partial lipodystrophy and insulin resistance.

Purpose of the Study:

• To investigate whether null variants in the PLIN1 gene are causative of lipodystrophy.
• To determine the clinical significance of PLIN1 null variants in individuals with or without lipodystrophy.

Main Methods:

• Sequencing of the PLIN1 gene in 2208 individuals as part of a targeted panel.
• Analysis of PLIN1 variant frequencies in the gnomAD database and the type 2 diabetes knowledge portal.

Main Results:

• PLIN1 null variants were identified in 6 of 2208 individuals, none exhibiting overt lipodystrophy.
• Analysis of the type 2 diabetes knowledge portal showed no association between PLIN1 null variants and lipodystrophy biomarkers.
• The frequency of PLIN1 null variants in gnomAD suggests they are too common to cause rare monogenic partial lipodystrophy.

Conclusions:

• Heterozygous PLIN1 variants predicted to cause haploinsufficiency are not causative of familial partial lipodystrophy.
• Diagnostic genetic testing laboratories should not report PLIN1 null variants as disease-causing.
• This aligns with other monogenic lipodystrophy causes where specific variant mechanisms are critical.