POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome

ABSTRACT Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%–15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome. We have systematically analysed the POLD1 gene in 50 patients initially diagnosed with Werner Syndrome in whom no mutations in the Werner helicase gene were identified. Indeed, we found eight patients with heterozygous POLD1 mutations, thereby identifying the most common molecular cause of atypical Werner Syndrome until now. In addition, we could more than double the overall number of progeroid patients with POLD1 mutations, which allowed to substantially expand and modify the clinical characterization of this new example of a segmental progeroid disorder.