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Diagnostic challenge in PLIN1-associated Familial Partial Lipodystrophy

Accepted version
Peer-reviewed

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Abstract

Context: Heterozygous frameshift variants in PLIN1 encoding perilipin-1, a key protein for lipid droplet formation and triglyceride metabolism, have been implicated in familial partial lipodystrophy type 4 (FPLD4), a rare entity with only 6 families reported worldwide. The pathogenicity of other PLIN1 null variants identified in patients with diabetes and/or hyperinsulinemia was recently questioned based on the absence of lipodystrophy in these individuals and on the elevated frequency of PLIN1 null variants in the general population. Objectives : To reevaluate the pathogenicity of PLIN1 frameshift variants in light of new data obtained in the largest series of patients with FPLD4. Methods : We performed histological, and molecular studies in patients referred to our French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity for lipodystrophy and/or insulin resistance, and carrying PLIN1 frameshift variants. Results: We identified two heterozygous PLIN1 frameshift variants segregating with the phenotype in 9 patients from 4 unrelated families. The FPLD4 stereotypical signs include postpubertal partial lipoatrophy of variable severity, muscular hypertrophy, acromegaloid features, PCOS and/or hirsutism, metabolic complications (hypertriglyceridemia, liver steatosis, insulin resistance, and diabetes), and disorganised subcutaneous fat lobules with fibrosis, and macrophage infiltration. Conclusions: These data suggest that some FPLD4-associated PLIN1 variants are indeed deleterious. Thus the evidence for the pathogenicity of each variant ought to be carefully considered prior to genetic counseling, especially given the importance of early diagnosis for optimal disease management. In this regard, we recommend detailed familial investigation, adipose tissue-focused examination, and follow-up of metabolic evolution.

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Journal Title

Journal of Clinical Endocrinology and Metabolism

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Journal ISSN

0021-972X

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Publisher

Oxford University Press

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All rights reserved
Sponsorship
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Wellcome Trust, MRC