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Genet Med. 2015 Nov;17(11):843-53. doi: 10.1038/gim.2014.210. Epub 2015 Feb 26.

The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.

Author information

1
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
2
Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
3
Department of Neurology, Division of Pediatric Neurology, Child Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
4
Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
5
Department of Pediatric Genetics, Academic Medical Center, Amsterdam, The Netherlands.
6
Department of Clinical Genetics, University Medical Center, University of Utrecht, Utrecht, The Netherlands.
7
Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
8
Department of Clinical Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands.
9
Department of Child Neurology, VU Medical Center, Amsterdam, The Netherlands.
10
Department of Neonatology, University Medical Center, University of Utrecht, Utrecht, The Netherlands.

Abstract

Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.

PMID:
25719457
DOI:
10.1038/gim.2014.210
[Indexed for MEDLINE]

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