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POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome
Author(s) -
Lessel Davor,
Hisama Fuki M.,
Szakszon Katalin,
Saha Bidisha,
Sanjuanelo Alexander Barrios,
Salbert Bonnie A.,
Steele Pamela D.,
Baldwin Jennifer,
Brown W. Ted,
Piussan Charles,
Plauchu Henri,
Szilvássy Judit,
Horkay Edit,
Högel Josef,
Martin George M.,
Herr Alan J.,
Oshima Junko,
Kubisch Christian
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22833
Subject(s) - biology , germline , genetics , germline mutation , mutation , cancer research , gene
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.