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Hum Genet. 2018 Dec;137(11-12):921-939. doi: 10.1007/s00439-018-1957-1. Epub 2018 Nov 19.

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

Author information

1
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. d.lessel@uke.de.
2
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
3
Center for Gerontology and Healthcare Research, Brown University, Providence, RI, USA.
4
Service de neurologie, CHU Ben Aknoun Alger, 2 route des deux Bassins, BenAknoun,, Algers, Algeria.
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.
6
Regional Center of Medical Genetics, Alessandrescu-Rusescu INSMC, Bucharest, Romania.
7
Department of Pediatrics, University of Debrecen, Debrecen, Hungary.
8
Department of Genetics, University Hospital Iasi, Iasi, Romania.
9
Instituto de Genética Humana, Facultad de Medicina, Pontificia Universidad Javeriana, Bogotá, Colombia.
10
Department of Genetics, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico.
11
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
12
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
13
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
14
Department of Genome Sciences, University of Washington, Seattle, USA.
15
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
16
Warren Alpert Medical School of Brown University, Providence, RI, USA.
17
Department of Pediatrics, Division of Genetics, Hasbro Children's Hospital, Providence, RI, USA.

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:

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

PMID:
30450527
DOI:
10.1007/s00439-018-1957-1
[Indexed for MEDLINE]

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