POLD1Germline 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.

Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent <i>de novo</i> mutation in the <i>POLD1</i> gene

“…The male-to-female ratio is 7:15. Among them, 15 patients had p.Ser605del, including our case; three patients had p.Arg507Cys [11][12][13][14][15][16] and only one had the novel mutation p.Ile1070Ans [16], and two related female patients had the recently identified mutation, p.Glu1067Lys [17]. Thus, the mutation detected in our patient, p.Ser605del, might constitute a hotspot for MDPL syndrome (Table 2, Fig.…”

“…2C). The deletion was reported as a pathogenic variant in patients with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL syndrome) [11][12][13][14][15][16][17]. In addition, no pathogenic mutations were also found in other lipodystrophy-related genes, including FBN1, LIPE, NK, PIK3R1, PSMB8, RTRF, and BANF1, as well as in the Werner helicase gene (WRN) by either Sanger sequencing or WES [21].…”

“…Thus, according to both the unique phenotypic mani- festations and the WES analysis, the patient was diagnosed as having MDPL syndrome; MIM #615381 in the Online Mendelian Inheritance in Man database [11][12][13][14][15][16][17].…”

“…To date, 21 patients with POLD1-related MDPL syndrome [11][12][13][14][15][16][17]26] have been reported in English publications, most frequently from European countries ( Table 2). The male-to-female ratio is 7:15.…”

“…Notably, a new causal factor of progressive lipodystrophy associated with MDPL syndrome has been identified [11][12][13][14][15][16][17]. Mutations in the polymerase delta 1 (POLD1) gene have been detected in several patients with MDPL, suggesting that MDPL is the result of POLD1 gene mutation.…”