Heterogeneidad genotipo-fenotipo entre pacientes con lipodistrofia portadores de variantes raras de POLD1

Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome is a rare, autosomal dominant disorder due to pathogenic heterozygous variants in POLD1. Clinical features of MDPL vary between patients, however, there is no previously reported genotype-phenotype association.

To report 14 new patients with lipodystrophy due to POLD1 variants and to compare phenotypic differences between those with p.Ser605del and missense variants.

Genetic sequencing was performed on DNA of 14 patients for POLD1 variants, including exome (n=10), genome (n=1) and candidate gene (n=3) sequencing. Comparisons of demographic, clinical features and metabolic complications between carriers of POLD1 p.Ser605del and missense variants in our cases and those reported in the literature were made using Fisher's exact test for categorical variables and Student's t-test for continuous variables.

A total of nine different POLD1 variants were identified in our patients, including three novel variants: p.Asp25Glufs*16, p.Arg507His, and p.Trp781Cys. Compared to individuals with missense variants (n=15), those with p.Ser605del (n=26) POLD1 variant had significantly increased prevalence of mandibular hypoplasia (57% vs 100%, respectively; p=0.015), small mouth (36% vs 100%, respectively; p=0.015), crowded teeth (44% vs 91%, respectively; p=0.046), and hypogonadism in males (0% vs. 92%, respectively; p=0.046). There were no differences in the prevalence of metabolic complications, such as diabetes, hypertriglyceridemia and hepatic steatosis in the two groups.

Subjects with heterozygous POLD1 p.Ser605del variant had typical MDPL with more severe phenotype compared to those with missense variants with atypical MDPL.