Genotype-Phenotype Heterogeneity Among Patients with Lipodystrophy Harboring Rare POLD1 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.