Titel Deelnemers "Korte inhoud" "The expanding phenotype of COL4A1 and COL4A2 mutations" "Marije Meuwissen, Dicky J. J. Halley, Liesbeth S. Smit, Maarten H. Lequin, Jan M. Cobben, Rene de Coo, Jeske van Harssel, Suzanne Sallevelt, Gwendolyn Woldringh, Marjo S. van der Knaap, Linda S. de Vries, Grazia M. S. Mancini" "Two proa1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proa2(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." "Atypical variants in COL1A1 and COL3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes : expanding the clinical phenotype based on additional case reports" "Marlies Colman, Marco Castori, Lucia Micale, Marco Ritelli, Marina Colombi, Neeti Ghali, Fleur Van Dijk, Luisa Marsili, Adrienne Weeks, Anthony Vandersteen, Andrea Rideout, Anne Legrand, Michael Frank, Tristan Mirault, Alessandro Ferraris, Niccolò Di Giosaffatte, Paola Grammatico, Juergen Grunert, Charissa Frank, Fransiska Malfait" "Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency" "Robin Lemmens, An Goris, Thomas Tousseyn, Philippe Demaerel, Wim Robberecht, Vincent Thijs" "Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant negative mechanism. Here we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency.Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed.In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both families nonsense mediated decay of the mutant COL4A1 mRNAs and a clear reduction of COL4A1 protein expression was demonstrated, indicating haploinsufficiency of COL4A1. Moreover thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations.These findings suggest haploinsufficiency, a different mechanism than the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease." "Novel variant in COL4A1 causes extensive prenatal intracranial hemorrhage and porencephaly" "Stefanie Brock, Alex Michotte, Elisa Done, Astrid Leus, Mieke Cannie, Kari De Pierre, Ramses Forsyth, Katrien Stouffs, Kathelijn Keymolen, Boyan Dimitrov, Annelies Fieuw, Anna Jansen, Kim Van Berkel" "Sporadic COL4A1 mutations with extensive prenatal porencephaly resembling hydranencephaly" "Marije Meuwissen, L.S. de Vries, H.A. Verbeek, M.H. Lequin, P.P. Govaert, R. Schot, F.M. Cowan, R. Hennekam, P. Rizzu, F.W. Verheijen, M.W. Wessels, G.M.S. Mancini" "COL4A2 mutation associated with familial porencephaly and small-vessel disease" "Elly Verbeeck, Marije Meuwissen, Frans W. Verheijen, et. al" "Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 3206delC fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors." "Intracerebral hemorrhage in a neonate with an intragenic COL4A2 duplication" "Saskia Koene, Cacha M.P.C.D. Peeters-Scholte, Jeroen Knijnenburg, Linda S. de Vries, Phebe N. Adama van Scheltema, Marije Meuwissen, Sylke J. Steggerda, Gijs W.E. Santen" "Intracerebral hemorrhage is rare in term born neonates. Besides several non-genetic risk factors, pathogenic variants in COL4A1 and COL4A2 have been described to play a role in the pathophysiology of neonatal intracerebral hemorrhage. To the best of our knowledge, no intragenic COL4A2 duplications have been reported in humans to date. We report a neonate with intracerebral hemorrhage and a de novo intragenic COL4A2 duplication. Although it is not clear yet whether this genetic factor fully explains the clinical phenotype, it may have contributed at least as a risk factor for cerebral hemorrhage. Screening for intragenic COL4A1 and COL4A2 duplications as part of collagen IV diagnostics should be considered as part of the fetal and neonatal work-up for unexplained cerebral hemorrhages and to collect more evidence of the pathogenicity of this genetic mechanism." "Deletion of the 5'exons of COL4A6 is not needed for the development of diffuse leiomyomatosis in patients with Alport syndrome" "Maria João Nabais Sá, Arjan P M de Brouwer, Rita Sousa, Fernando Teixeira e Costa, Maria José Brito, Fernanda Carvalho, Márcia Rodrigues, Francisco Teixeira de Sousa, Joana Felgueiras, Fernando Neves, Adelino Carvalho, Umbelina Ramos, José Ramón Vizcaíno, Susana Alves, Filipa Carvalho, Guy Froyen, João Paulo Oliveira" "BACKGROUND: Alport syndrome (AS), a hereditary type IV collagen nephropathy, is a major cause of end-stage renal disease in young people. About 85% of the cases are X-linked (ATS), due to mutations in the COL4A5 gene. Rarely, families have a contiguous gene deletion comprising at least exon 1 of COL4A5 and the first exons of COL4A6, associated with the development of diffuse leiomyomatosis (ATS-DL). We report three novel deletions identified in families with AS, one of which challenges the current concepts on genotype-phenotype correlations of ATS/ATS-DL.METHODS: In the setting of a multicentric study aiming to describe the genetic epidemiology and molecular pathology of AS in Portugal, three novel COL4A5 deletions were identified in two families with x-linked Alport syndrome (ATS) and in one family with ATS-DL. These mutations were initially detected by PCR and Multiplex Ligation-dependent Probe Amplification, and further mapped by high-resolution X chromosome-specific oligo-array and PCR.RESULTS: In the ATS-DL family, a COL4A5 deletion spanning exons 2 through 51, extending distally beyond COL4A5 but proximally not into COL4A6, segregated with the disease phenotype. A COL4A5 deletion encompassing exons 2 through 29 was identified in one of the ATS families. In the second ATS family, a deletion of exon 13 of COL4A5 through exon 3 of COL4A6 was detected.CONCLUSIONS: These observations suggest that deletion of the 5' exons of COL4A6 and of the common promoter of the COL4A5 and COL4A6 genes is not essential for the development of leiomyomatosis in patients with ATS, and that COL4A5_COL4A6 deletions extending into COL4A6 exon 3 may not result in ATS-DL." "Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients." "K.p. Hoornaert, I. Vereecke, C. Dewinter, T. Rosenberg, F.a. Beemer, J.g. Leroy, L. Bendix, E. Björck, Maryse Bonduelle, O. Boute, V. Cormier-Daire, C.e.m. De Die-Smulders, A. Dieux-Coeslier, H. Dollfus, M. Elting, A. Green, V.i. Guerci, R.c. Hennekam, Y. Hilhorts-Hofstee, M. Holder, C. Hoyng, K.j. Jones, D. Josifova, I. Kaitila, S. Kjaergaard, Y.h. Kroes, K. Lagerstedt, M. Lees, M. Lemerrer, C. Magnani, C. Marcelis, L. Martorell, M. Mathieu, M. Mcentagart, A. Mendicino, J. Morton, G. Orazio, V. Paquis, O. Reish, K.o. Simola, S.f. Smithson, K.i. Temple, E. Van Aken, Y. Van Bever, J. Van Den Ende, J.m. Van Hagen, L. Zelante, R. Zordania, A. De Paepe, B.p. Leroy, M. De Buyzere, P.j. Coucke, G.r. Mortier" "Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome." "Spondyloperipheral dysplasia as the mosaic form of platyspondylic lethal skeletal dyplasia torrance type in mother and fetus with the same COL2A1 mutation" "Julie Désir, Marie Cassart, Catherine Donner, Paul Coucke, Marc Abramowicz, Geert Mortier"