PLIN1 Haploinsufficiency Is Not Associated With Lipodystrophy

J Clin Endocrinol Metab. 2018 Sep 1;103(9):3225-3230. doi: 10.1210/jc.2017-02662.


Context: Monogenic partial lipodystrophy is a genetically heterogeneous disease where only variants with specific genetic mechanisms are causative. Three heterozygous protein extending frameshift variants in PLIN1 have been reported to cause a phenotype of partial lipodystrophy and insulin resistance.

Objective: We investigated if null variants in PLIN1 cause lipodystrophy.

Methods: As part of a targeted sequencing panel test, we sequenced PLIN1 in 2208 individuals. We also investigated the frequency of PLIN1 variants in the gnomAD database, and the type 2 diabetes knowledge portal.

Results: We identified 6/2208 (1 in 368) individuals with a PLIN1 null variant. None of these individuals had clinical or biochemical evidence of overt lipodystrophy. Additionally, 14/17,000 (1 in 1214) individuals with PLIN1 null variants in the type 2 diabetes knowledge portal showed no association with biomarkers of lipodystrophy. PLIN1 null variants occur too frequently in gnomAD (126/138,632; 1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy.

Conclusions: Our study suggests that heterozygous variants that are predicted to result in PLIN1 haploinsufficiency are not a cause of familial partial lipodystrophy and should not be reported as disease-causing variants by diagnostic genetic testing laboratories. This finding is in keeping with other known monogenic causes of lipodystrophy, such as PPARG and LMNA, where only variants with specific genetic mechanisms cause lipodystrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / blood
  • Child
  • Databases, Genetic
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Haploinsufficiency*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Lipodystrophy, Familial Partial / genetics*
  • Male
  • Middle Aged
  • Pedigree
  • Perilipin-1 / genetics*
  • Phenotype


  • Biomarkers
  • PLIN1 protein, human
  • Perilipin-1