Lessel, Davor ORCID: 0000-0003-4496-244X, Ozel, Ayse Bilge, Campbell, Susan E., Saadi, Abdelkrim, Arlt, Martin F., McSweeney, Keisha Melodi, Plaiasu, Vasilica, Szakszon, Katalin, Szollos, Anna, Rusu, Cristina, Rojas, Armando J., Lopez-Valdez, Jaime, Thiele, Holger, Nuernberg, Peter, Nickerson, Deborah A., Bamshad, Michael J., Li, Jun Z., Kubisch, Christian, Glover, Thomas W. and Gordon, Leslie B. (2018). 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 (11-12). S. 921 - 940. NEW YORK: SPRINGER. ISSN 1432-1203

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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 (similar to 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lessel, DavorUNSPECIFIEDorcid.org/0000-0003-4496-244XUNSPECIFIED
Ozel, Ayse BilgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campbell, Susan E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saadi, AbdelkrimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arlt, Martin F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McSweeney, Keisha MelodiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plaiasu, VasilicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szakszon, KatalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szollos, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rusu, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rojas, Armando J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Valdez, JaimeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickerson, Deborah A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bamshad, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, Jun Z.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glover, Thomas W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gordon, Leslie B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-163834
DOI: 10.1007/s00439-018-1957-1
Journal or Publication Title: Hum. Genet.
Volume: 137
Number: 11-12
Page Range: S. 921 - 940
Date: 2018
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-1203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOMIC INSTABILITY; GENESMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16383

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