title: The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.
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.
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: Marije E C
authors.initials: ME
authors.lastname: Meuwissen
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dicky J J
authors.identifier: http://orcid.org/0000-0002-5571-1024
authors.initials: DJ
authors.lastname: Halley
authors.affiliation: Department of Neurology, Division of Pediatric Neurology, Child Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Liesbeth S
authors.identifier: http://orcid.org/0000-0003-4176-9310
authors.initials: LS
authors.lastname: Smit
authors.affiliation: Department of Radiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maarten H
authors.initials: MH
authors.lastname: Lequin
authors.affiliation: Department of Pediatric Genetics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Cobben
authors.affiliation: Department of Neurology, Division of Pediatric Neurology, Child Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: René
authors.identifier: http://orcid.org/0000-0003-0533-7422
authors.initials: R
authors.lastname: de Coo
authors.affiliation: Department of Clinical Genetics, University Medical Center, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Jeske
authors.initials: J
authors.lastname: van Harssel
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sallevelt
authors.affiliation: Department of Clinical Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands.
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Woldringh
authors.affiliation: Department of Child Neurology, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.affiliation: Department of Neonatology, University Medical Center, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Linda S
authors.identifier: http://orcid.org/0000-0002-7282-8304
authors.initials: LS
authors.lastname: de Vries
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Grazia M S
authors.identifier: http://orcid.org/0000-0002-1211-9979
authors.initials: GM
authors.lastname: Mancini
mesh_terms: D000483:Alleles; D000869:Anterior Eye Segment / Q000002:abnormalities; D001921:Brain / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000175:diagnosis / Q000235:genetics; D015331:Cohort Studies; D024141:Collagen Type IV / Q000235:genetics*; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics; D015785:Eye Diseases, Hereditary; D005190:Family; D023061:Gene Order; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D007969:Leukomalacia, Periventricular / Q000175:diagnosis / Q000235:genetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D065708:Porencephaly / Q000175:diagnosis / Q000235:genetics
chemical_list: C547475:COL4A1 protein, human; C502625:COL4A2 protein, human; D024141:Collagen Type IV