POLD1 – Mandibular hypoplasia–deafness–progeroid syndrome (MDPL)

Mandibular hypoplasia–deafness–progeroid syndrome (MDPL) is a rare autosomal dominant disorder characterized by progressive lipodystrophy, mandibular hypoplasia, beaked nasal ridge, crowded dentition, sensorineural hearing loss, hepatic steatosis, hypertriglyceridemia and insulin resistance. Affected individuals present with a bird‐like facies, progeroid facial features and metabolic complications including diabetes and hepatomegaly.

MDPL is caused by heterozygous de novo mutations in POLD1, which encodes the catalytic subunit of DNA polymerase δ. In the initial series of 9 MDPL patients, an in‐frame deletion c.1812_1814del (p.Ser605del) was reported in 4 individuals ([PMID:25131834]). Subsequent studies have identified this recurrent in‐frame deletion in at least 16 additional unrelated probands and a spectrum of missense variants affecting the exonuclease and polymerase domains ([PMID:29199204]).

All pathogenic POLD1 variants in MDPL are heterozygous and occur de novo with autosomal dominant inheritance; no evidence of multigenerational segregation has been observed, consistent with a mutation‐limited cohort (affected_relatives = 0). The recurrent c.1812_1814del (p.Ser605del) is the most frequent allele; other reported changes include c.1519C>T (p.Arg507Cys) and c.3185A>G (p.Gln1062Arg).

Functional studies in patient‐derived fibroblasts carrying p.Ser605del demonstrate severe nuclear envelope anomalies, micronuclei formation, prelamin A accumulation, altered cell growth, cellular senescence and persistence of DNA damage following cisplatin exposure, confirming polymerase δ dysfunction ([PMID:30388038]).

Mechanistic analyses reveal that polymerase‐active site mutations such as c.3244C>T (p.Arg1082Cys) abolish DNA synthesis activity while sparing exonuclease function, leading to tissue‐specific effects on adipose homeostasis and progeroid features ([PMID:23770608]).

Collectively, the presence of ≥ 21 unrelated de novo POLD1 variants in MDPL patients, concordant segregation and robust cellular phenotypes support a Strong gene–disease association. Functional data reach a Moderate level under ClinGen criteria. Genetic testing for POLD1 mutations is recommended in patients with suggestive multisystem lipodystrophy and progeroid presentations. Key take–home: heterozygous de novo POLD1 mutations cause autosomal dominant MDPL syndrome, enabling precise molecular diagnosis and informing patient management.

References

• Metabolism: clinical and experimental • 2014 • Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome. [PMID:25131834]
• Endocrine journal • 2018 • Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene. [PMID:29199204]
• DNA and cell biology • 2018 • Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in POLD1 Gene. [PMID:30388038]
• Nature genetics • 2013 • An in‐frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. [PMID:23770608]
• Metabolism: clinical and experimental • 2017 • Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in MDPL syndrome. [PMID:28521875]

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