title: 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.
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Davor
authors.initials: D
authors.lastname: Lessel
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Fuki M
authors.initials: FM
authors.lastname: Hisama
authors.affiliation: Department of Pediatrics, University of Debrecen, Debrecen, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Szakszon
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Saha
authors.affiliation: Department of Medicine, Universidad Del Norte-CINPE Group, Barranquilla, Colombia.
authors.forename: Alexander Barrios
authors.initials: AB
authors.lastname: Sanjuanelo
authors.affiliation: Geisinger Medical Center, Danville, Pennsylvania.
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Salbert
authors.affiliation: Geisinger Medical Center, Danville, Pennsylvania.
authors.forename: Pamela D
authors.initials: PD
authors.lastname: Steele
authors.affiliation: Department of Dermatology, University of Minnesota, Minnesota.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baldwin
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York.
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
authors.affiliation: Pediatric Genetics, University of Amiens, Amiens, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Piussan
authors.affiliation: Département de Génétique, Université Claude Bernard Lyon 1 et Hôpital Louis Pradel, Hospices Civils de Lyon, F-69977, Bron CEDEX, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Plauchu
authors.affiliation: Department of Oto-Laryngology and Head and Neck Surgery, University of Debrecen, Debrecen, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Szilvássy
authors.affiliation: Diagnoscan Hungary, Debrecen, Hungary.
authors.forename: Edit
authors.initials: E
authors.lastname: Horkay
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Högel
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Herr
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D002461:Cell Line, Transformed; D002648:Child; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D003057:Cockayne Syndrome / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004258:DNA Polymerase III / Q000737:chemistry / Q000235:genetics*; D003937:Diagnosis, Differential; D019066:Facies; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010641:Phenotype; D011487:Protein Conformation; D012042:Registries; D014898:Werner Syndrome / Q000175:diagnosis*; D055815:Young Adult
chemical_list: C434055:POLD1 protein, human; D004258:DNA Polymerase III
keywords: POLD1; Werner syndrome; deafness; mandibular hypoplasia; progeroid features (MDP) syndrome