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Human Genetics

, Volume 137, Issue 11–12, pp 921–939 | Cite as

Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann–Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations

  • Davor Lessel
  • Ayse Bilge Ozel
  • Susan E. Campbell
  • Abdelkrim Saadi
  • Martin F. Arlt
  • Keisha Melodi McSweeney
  • Vasilica Plaiasu
  • Katalin Szakszon
  • Anna Szőllős
  • Cristina Rusu
  • Armando J. Rojas
  • Jaime Lopez-Valdez
  • Holger Thiele
  • Peter Nürnberg
  • Deborah A. Nickerson
  • Michael J. Bamshad
  • Jun Z. Li
  • Christian Kubisch
  • Thomas W. Glover
  • Leslie B. Gordon
Original Investigation

Abstract

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson–Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann–Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

Keywords

Juvenile segmental progeroid syndrome Hutchinson–Gilford progeria syndrome Wiedemann–Rautenstrauch progeroid syndrome POLR3A PYCR1 

Notes

Acknowledgements

We thank the patients and their families for participation in this study. This work was funded in part by local funding (Forschungsförderungsfonds der Medizinischen Fakultät der Universitätsklinikum Hamburg-Eppendorf [FFM]) and the Deutsche Forschungsgemeinschaft (LE4223/1–1) to DL, The University of Michigan Center for Genomics in Health and Disease to TWG, and by The Progeria Research Foundation. UW-CMG Acknowledgement Statement: Sequencing of parental DNA from individuals 1–5 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) which was funded by the National Human Genome Research Institute and the National Heart, Lung and Blood Institute grant 2UM1HG006493 to Drs. Debbie Nickerson, Michael Bamshad, and Suzanne Leal.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants

The study has ongoing approval from the Hasbro Children’s Hospital and the University Medical Center Hamburg-Eppendorf Institutional Review Boards. The study was performed in accordance with the Declaration of Helsinki protocols.

Informed consent

All biological samples were obtained following written informed consent from studied individuals or their legal representatives.

Supplementary material

439_2018_1957_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 19 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Davor Lessel
    • 1
  • Ayse Bilge Ozel
    • 2
  • Susan E. Campbell
    • 3
  • Abdelkrim Saadi
    • 4
  • Martin F. Arlt
    • 2
  • Keisha Melodi McSweeney
    • 5
  • Vasilica Plaiasu
    • 6
  • Katalin Szakszon
    • 7
  • Anna Szőllős
    • 7
  • Cristina Rusu
    • 8
  • Armando J. Rojas
    • 9
  • Jaime Lopez-Valdez
    • 10
  • Holger Thiele
    • 11
  • Peter Nürnberg
    • 11
    • 12
    • 13
  • Deborah A. Nickerson
    • 14
  • Michael J. Bamshad
    • 14
  • Jun Z. Li
    • 2
  • Christian Kubisch
    • 1
  • Thomas W. Glover
    • 2
  • Leslie B. Gordon
    • 15
    • 16
  1. 1.Institute of Human GeneticsUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of Human GeneticsUniversity of MichiganAnn ArborUSA
  3. 3.Center for Gerontology and Healthcare ResearchBrown UniversityProvidenceUSA
  4. 4.Service de neurologieCHU Ben Aknoun AlgerBenAknoun,Algeria
  5. 5.Oak Ridge Institute for Science and EducationOffice of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  6. 6.Regional Center of Medical GeneticsAlessandrescu-Rusescu INSMCBucharestRomania
  7. 7.Department of PediatricsUniversity of DebrecenDebrecenHungary
  8. 8.Department of GeneticsUniversity Hospital IasiIasiRomania
  9. 9.Instituto de Genética Humana, Facultad de MedicinaPontificia Universidad JaverianaBogotáColombia
  10. 10.Department of GeneticsCentenario Hospital Miguel HidalgoAguascalientesMexico
  11. 11.Cologne Center for GenomicsUniversity of CologneCologneGermany
  12. 12.Center for Molecular Medicine CologneUniversity of CologneCologneGermany
  13. 13.Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated DiseasesUniversity of CologneCologneGermany
  14. 14.Department of Genome SciencesUniversity of WashingtonSeattleUSA
  15. 15.Warren Alpert Medical School of Brown UniversityProvidenceUSA
  16. 16.Department of Pediatrics, Division of GeneticsHasbro Children’s HospitalProvidenceUSA

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