POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome |
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| Authors: | Davor Lessel Fuki M. Hisama Katalin Szakszon Bidisha Saha Alexander Barrios Sanjuanelo Bonnie A. Salbert Pamela D. Steele Jennifer Baldwin W. Ted Brown Henri Plauchu Judit Szilvássy Edit Horkay Josef Högel George M. Martin Alan J. Herr Junko Oshima Christian Kubisch |
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| Affiliation: | 1. Institute of Human Genetics, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;2. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington;3. Department of Pediatrics, University of Debrecen, Debrecen, Hungary;4. Department of Pathology, University of Washington, Seattle, Washington;5. Department of Medicine, Universidad Del Norte‐CINPE Group, Barranquilla, Colombia;6. Geisinger Medical Center, Danville, Pennsylvania;7. Department of Dermatology, University of Minnesota, Minnesota;8. New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York;9. Département de Génétique, Université Claude Bernard Lyon 1 et H?pital Louis Pradel, Hospices Civils de Lyon, Bron CEDEX, France;10. Department of Oto‐Laryngology and Head and Neck Surgery, University of Debrecen, Debrecen, Hungary;11. Diagnoscan Hungary, Debrecen, Hungary;12. Institute of Human Genetics, University of Ulm, Ulm, Germany |
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| 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. |
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| Keywords: | mandibular hypoplasia deafness progeroid features (MDP) syndrome POLD1 Werner syndrome |
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