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Updated: Feb 28, 2026

Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
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Genotype-phenotype heterogeneity among patients with lipodystrophy harboring rare POLD1 variants

Fieke W Hoff1, Chao Xing2,3,4, Chun-Yuan Huang2

  • 1Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

The Journal of Clinical Endocrinology and Metabolism
|February 26, 2026
PubMed
Abstract

Insights

Patients with the POLD1 p.Ser605del variant show a more severe form of Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome compared to those with other POLD1 missense variants.

Area of Science:

  • Genetics
  • Human Physiology
  • Rare Diseases

Background:

  • Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder.
  • Pathogenic heterozygous variants in POLD1 cause MDPL syndrome.
  • Existing literature lacks genotype-phenotype associations for MDPL.

Purpose of the Study:

  • To identify and characterize POLD1 variants in 14 new patients with lipodystrophy.
  • To compare the clinical and metabolic phenotypes between patients with POLD1 p.Ser605del and missense variants.

Main Methods:

  • Genetic sequencing (exome, genome, candidate gene) was performed on 14 patients.
  • Phenotypic data were collected and compared between variant groups.
  • Statistical analyses included Fisher's exact test and Student's t-test.

Main Results:

  • Nine different POLD1 variants were identified, including three novel ones.
  • Patients with the p.Ser605del variant exhibited significantly higher rates of mandibular hypoplasia, small mouth, crowded teeth, and male hypogonadism.
  • No significant differences in metabolic complications like diabetes or hepatic steatosis were observed between groups.

Conclusions:

  • The POLD1 p.Ser605del variant is associated with a more severe, typical MDPL phenotype.
  • Missense POLD1 variants are linked to atypical MDPL presentations.
  • This study establishes a genotype-phenotype correlation for POLD1-related disorders.
Keywords:
MDPLPOLD1deafnesslipodystrophymandibular hypoplasiaprogeroid features

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