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

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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.

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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.

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Authors and Affiliations

  1. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Davor Lessel & Christian Kubisch

  2. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    Ayse Bilge Ozel, Martin F. Arlt, Jun Z. Li & Thomas W. Glover

  3. Center for Gerontology and Healthcare Research, Brown University, Providence, RI, USA

    Susan E. Campbell

  4. Service de neurologie, CHU Ben Aknoun Alger, 2 route des deux Bassins, BenAknoun,, Algers, Algeria

    Abdelkrim Saadi

  5. Oak Ridge Institute for Science and Education, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, 20993, Silver Spring, MD, USA

    Keisha Melodi McSweeney

  6. Regional Center of Medical Genetics, Alessandrescu-Rusescu INSMC, Bucharest, Romania

    Vasilica Plaiasu

  7. Department of Pediatrics, University of Debrecen, Debrecen, Hungary

    Katalin Szakszon & Anna Szőllős

  8. Department of Genetics, University Hospital Iasi, Iasi, Romania

    Cristina Rusu

  9. Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia

    Armando J. Rojas

  10. Department of Genetics, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico

    Jaime Lopez-Valdez

  11. Cologne Center for Genomics, University of Cologne, Cologne, Germany

    Holger Thiele & Peter Nürnberg

  12. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    Peter Nürnberg

  13. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

    Peter Nürnberg

  14. Department of Genome Sciences, University of Washington, Seattle, USA

    Deborah A. Nickerson & Michael J. Bamshad

  15. Warren Alpert Medical School of Brown University, Providence, RI, USA

    Leslie B. Gordon

  16. Department of Pediatrics, Division of Genetics, Hasbro Children’s Hospital, Providence, RI, USA

    Leslie B. Gordon

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  1. Davor Lessel
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  2. Ayse Bilge Ozel
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  3. Susan E. Campbell
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  15. Deborah A. Nickerson
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  16. Michael J. Bamshad
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  17. Jun Z. Li
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  18. Christian Kubisch
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  19. Thomas W. Glover
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  20. Leslie B. Gordon
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Correspondence to Davor Lessel.

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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.

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

Additional information

As this manuscript went to press, a further study independently confirmed biallelic POLR3A mutations as the cause of Wiedemann–Rautenstrauch syndrome. Moreover, that study report on the identical patient, their subject 3, as the herein presented individual 4 (Wambach et al. 2018).

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Lessel, D., Ozel, A.B., Campbell, S.E. et al. Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann–Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Hum Genet 137, 921–939 (2018). https://doi.org/10.1007/s00439-018-1957-1

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