CLINICAL REPORT A Novel Mutation in COL4A1 Gene: A Possible Cause Of Early Postnatal Cerebrovascular Events Alice Decio, 1 Davide Tonduti, 1 Anna Pichiecchio, 2 Annalisa Vetro, 3 Roberto Ciccone, 4,5 Ivan Limongelli, 4 Roberto Giorda, 6 Lorella Caffi, 7 Umberto Balottin, 1,8 Orsetta Zuffardi, 5 and Simona Orcesi 8 * 1 Child Neurology and Psychiatry Unit, Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy 2 Department of Neuroradiology, C. Mondino National Neurological Institute, Pavia, Italy 3 Biotechnology Research Laboratory, IRCCS Policlinico San Matteo, Pavia, Italy 4 Center for Genetic and Therapeutic Approaches, C. Mondino National Neurological Institute, Pavia, Italy 5 Department of Molecular Medicine, University of Pavia, Pavia, Italy 6 Molecular Biology Laboratory, IRCCS Scientific Institute Eugenio Medea, Bosisio Parini, Italy 7 Child Neurology and Psychiatry Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy 8 Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, Pavia, Italy Manuscript Received: 22 May 2014; Manuscript Accepted: 14 November 2014 COL4A1 is located in humans on chromosome13q34 and it encodes the alpha 1 chain of type IV collagen, a component of basal membrane. It is expressed mainly in the brain, muscles, kidneys and eyes. Different COL4A1 mutations have been reported in many patients who present a very wide spectrum of clinical symptoms. They typically show a multisystemic phe- notype. Here we report on the case of a patient carrying a novel de novo splicing mutation of COL4A1 associated with a distinctive clinical picture characterized by onset in infancy and an unusual evolution of the neuroradiological features. At three months of age, the child was diagnosed with a congenital cataract, while his brain MRI was normal. Over the following years, the patient developed focal epilepsy, mild diplegia, asymptomatic micro- hematuria, raised creatine kinase levels, MRI white matter abnormalities and brain calcification on CT. During the neuro- radiological follow-up the extension and intensity of the brain lesions progressively decreased. The significance of a second variant in COL4A1 carried by the child and inherited from his father remains to be clarified. In conclusion, our patient shows new aspects of this collagenopathy and possibly a COL4A1 compound heterozygosity. Ó 2015 Wiley Periodicals, Inc. Key words: COL4A1 gene; infants; leukoencephalopathy; cerebral calcification INTRODUCTION COL4A1 encodes the alpha 1 chain of collagen type IV, a funda- mental component of vascular basal membrane. The gene is expressed mainly in the brain, muscles, kidneys and eyes. Type IV collagen is made from six types of homologous chains indicated as alpha1–6. These chains assemble as heterotrimers. Every tissue containing collagen type IV in its basal membrane has a distinctive expression of alpha chains. Alpha chain hetero- trimers associate in dimers and then in tetramers, forming the complex collagen type IV suprastructure [Volonghi et al., 2010]. COL4A1 is located in humans on chromosome 13q34. Different COL4A1 mutations have been reported in numerous patients who present a very wide spectrum of clinical symptoms; no clear genotype-phenotype association has been found [Gould et al., 2005; Breedveld et al., 2006; Gould et al., 2006; Van der Knaap How to Cite this Article: Decio A,Tonduti D, Pichiecchio A, Vetro A, Ciccone R, Limongelli I, Giorda R, Caffi L, Balottin U, Zuffardi O, Orcesi S. 2015. A novel mutation in COL4A1 gene: A possible cause of early postnatal cerebrovascular events. Am J Med Genet Part A. 9999:1–6. Conflicts of interest: none. Grant sponsor: Regione Lombardia government; Grant number: DGRS 13465–22/12/2010; Grant sponsor: PRIN 2010–2011; Grant number: 20108WT59Y_003. � Correspondence to: Simona Orcesi, M.D., Child Neurology and Psychiatry Unit, C. Mondino National Neurological Institute, via Mondino 2, 27100 Pavia, Italy. E-mail: simona.orcesi@mondino.it Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36907 Ó 2015 Wiley Periodicals, Inc. 1