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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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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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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DOI: https://doi.org/10.1007/s00439-018-1957-1