Short communication| Volume 352, ISSUE 1-2, P99-104, May 15, 2015

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Two families with novel missense mutations in COL4A1: When diagnosis can be missed

Published:April 07, 2015DOI:


      • COL4A1-related disorders include a wide range of neurological diseases associated with high intra-familial variability.
      • We describe two novel mutations confirming high intra-familial variability.
      • Very mild phenotypes, apparent incomplete penetrance, and de novo cases are characteristics of these diseases.


      Mutations in COL4A1, encoding one of the six collagen type IV proteins, cover a wide spectrum of autosomal dominant overlapping phenotypes including porencephaly, small-vessel disease and hemorrhagic stroke, leukoencephalopathy, hereditary angiopathy with nephropathy, aneurysms and muscle cramp (HANAC) syndrome, and Walker–Warburg syndrome. Over 50 mutations are known, mainly being missense changes. Intra- and inter-familial variability has been reported.
      We studied two Italian families in which the proband had a clinical diagnosis of COL4A1-related disorder. We found two novel mutations (c.1249G>C; p.Gly417Arg and c.2662G>C; p.Gly888Arg). Both involved highly conserved amino acids and were predicted as being deleterious by bioinformatics tools. The c.1249G>C (p.Gly417Arg) segregated in four subjects with variable neurological phenotypes, namely leukoencephalopathy with muscle symptoms, brain small-vessel disease, and mild infantile encephalopathy. A fourth case was a carrier of the mutation without any neurological symptoms and an MRI with a specific white matter anomaly. The c.2662G>C (p.Gly888Arg) mutation was de novo in the proband. After a temporary motor impairment at age 14, the subject complained of mild imbalance at age 30, during the third trimester of her twin pregnancy, when an anomaly of the left brain hemisphere was documented in one fetus. Both her male dizygotic twins presented a severe motor delay, early convulsions, and leukoencephalopathy, and were carriers of the mutation.
      In summary, we confirm that high intra-familial variability of COL4A1 mutations with very mild phenotypes, the apparent incomplete penetrance, and de novo changes may become a “dilemma” for clinicians and genetic counselors.


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        • Glentis A.
        • Gurchenkov V.
        • Vignjevic D.M.
        Assembly, heterogeneity, and breaching of the basement membranes.
        Cell Adh Migr. 2014; 8
        • Kuo D.S.
        • Labelle-Dumais C.
        • Gould D.B.
        COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets.
        Hum Mol Genet. 2012; 21: R97-R110
        • Khoshnoodi J.
        • Pedchenko V.
        • Hudson B.G.
        Mammalian collagen IV.
        Microsc Res Tech. 2008; 71: 357-370
        • Hudson B.G.
        The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family.
        J Am Soc Nephrol. 2004; 15: 2514-2527
        • Zhou J.
        • Gregory M.C.
        • Hertz J.M.
        • Barker D.F.
        • Atkin C.
        • Spencer E.S.
        • et al.
        Mutations in the codon for a conserved arginine-1563 in the COL4A5 collagen gene in Alport syndrome.
        Kidney Int. 1993; 43: 722-729
        • Zhou J.
        • Mochizuki T.
        • Smeets H.
        • Antignac C.
        • Laurila P.
        • de Paepe A.
        • et al.
        Deletion of the paired alpha 5(IV) and alpha 6(IV) collagen genes in inherited smooth muscle tumors.
        Science. 1993; 261: 1167-1169
        • Rost S.
        • Bach E.
        • Neuner C.
        • Nanda I.
        • Dysek S.
        • Bittner R.E.
        • et al.
        Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6.
        Eur J Hum Genet. 2014; 22: 208-215
        • Gould D.B.
        • Phalan F.C.
        • Breedveld G.J.
        • van Mil S.E.
        • Smith R.S.
        • Schimenti J.C.
        • et al.
        Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly.
        Science. 2005; 308: 1167-1171
        • Yoneda Y.
        • Haginoya K.
        • Arai H.
        • Yamaoka S.
        • Tsurusaki Y.
        • Doi H.
        • et al.
        De novo and inherited mutations in COL4A2, encoding the type IV collagen alpha2 chain cause porencephaly.
        Am J Hum Genet. 2012; 90: 86-90
        • Gould D.B.
        • Phalan F.C.
        • van Mil S.E.
        • Sundberg J.P.
        • Vahedi K.
        • Massin P.
        • et al.
        Role of COL4A1 in small-vessel disease and hemorrhagic stroke.
        N Engl J Med. 2006; 354: 1489-1496
        • Jeanne M.
        • Labelle-Dumais C.
        • Jorgensen J.
        • Kauffman W.B.
        • Mancini G.M.
        • Favor J.
        • et al.
        COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke.
        Am J Hum Genet. 2012; 90: 91-101
        • Corlobe A.
        • Tournier-Lasserve E.
        • Mine M.
        • Menjot de Champfleur N.
        • Carra Dalliere C.
        • Ayrignac X.
        • et al.
        COL4A1 mutation revealed by an isolated brain hemorrhage.
        Cerebrovasc Dis. 2013; 35: 593-594
        • Sibon I.
        • Coupry I.
        • Menegon P.
        • Bouchet J.P.
        • Gorry P.
        • Burgelin I.
        • et al.
        COL4A1 mutation in Axenfeld–Rieger anomaly with leukoencephalopathy and stroke.
        Ann Neurol. 2007; 62: 177-184
        • Plaisier E.
        • Gribouval O.
        • Alamowitch S.
        • Mougenot B.
        • Prost C.
        • Verpont M.C.
        • et al.
        COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps.
        N Engl J Med. 2007; 357: 2687-2695
        • Labelle-Dumais C.
        • Dilworth D.J.
        • Harrington E.P.
        • de Leau M.
        • Lyons D.
        • Kabaeva Z.
        • et al.
        COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker–Warburg syndrome in humans.
        PLoS Genet. 2011; 7: e1002062
        • Deml B.
        • Reis L.M.
        • Maheshwari M.
        • Griffis C.
        • Bick D.
        • Semina E.V.
        Whole exome analysis identifies dominant COL4A1 mutations in patients with complex ocular phenotypes involving microphthalmia.
        Clin Genet. 2014; 86: 475-481
        • Plaisier E.
        • Chen Z.
        • Gekeler F.
        • Benhassine S.
        • Dahan K.
        • Marro B.
        • et al.
        Novel COL4A1 mutations associated with HANAC syndrome: a role for the triple helical CB3[IV] domain.
        Am J Med Genet A. 2010; 152A: 2550-2555
        • Verbeek E.
        • Meuwissen M.E.
        • Verheijen F.W.
        • Govaert P.P.
        • Licht D.J.
        • Kuo D.S.
        • et al.
        COL4A2 mutation associated with familial porencephaly and small-vessel disease.
        Eur J Hum Genet. 2012; 20: 844-851
        • Gupta M.C.
        • Graham P.L.
        • Kramer J.M.
        Characterization of alpha1(IV) collagen mutations in Caenorhabditis elegans and the effects of alpha1 and alpha2(IV) mutations on type IV collagen distribution.
        J Cell Biol. 1997; 137: 1185-1196
        • Sibley M.H.
        • Graham P.L.
        • von Mende N.
        • Kramer J.M.
        Mutations in the alpha 2(IV) basement membrane collagen gene of Caenorhabditis elegans produce phenotypes of differing severities.
        EMBO J. 1994; 13: 3278-3285
        • Renieri A.
        • Meroni M.
        • Sessa A.
        • Battini G.
        • Serbelloni P.
        • Torri Tarelli L.
        • et al.
        Variability of clinical phenotype in a large Alport family with Gly 1143 Ser change of collagen alpha 5(IV)-chain.
        Nephron. 1994; 67: 444-449
      1. Wallis Y, Payne S, McAnulty C, Bodmer D, Sistermans E, Robertson K, et al. Practice guidelines for the evaluation of pathogenicity and reporting of sequence variants in clinical molecular genetics. In: ACGS, editor. 2013.

        • Vermeulen R.J.
        • Peeters-Scholte C.
        • Van Vugt J.J.
        • Barkhof F.
        • Rizzu P.
        • van der Schoor S.R.
        • et al.
        Fetal origin of brain damage in 2 infants with a COL4A1 mutation: fetal and neonatal MRI.
        Neuropediatrics. 2011; 42: 1-3
        • de Vries L.S.
        • Koopman C.
        • Groenendaal F.
        • Van Schooneveld M.
        • Verheijen F.W.
        • Verbeek E.
        • et al.
        COL4A1 mutation in two preterm siblings with antenatal onset of parenchymal hemorrhage.
        Ann Neurol. 2009; 65: 12-18
        • Meuwissen M.E.
        • de Vries L.S.
        • Verbeek H.A.
        • Lequin M.H.
        • Govaert P.P.
        • Schot R.
        • et al.
        Sporadic COL4A1 mutations with extensive prenatal porencephaly resembling hydranencephaly.
        Neurology. 2011; 76: 844-846
        • Shah S.
        • Kumar Y.
        • McLean B.
        • Churchill A.
        • Stoodley N.
        • Rankin J.
        • et al.
        A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly.
        Eur J Paediatr Neurol. 2010; 14: 182-187
        • Khan U.
        • Porteous L.
        • Hassan A.
        • Markus H.S.
        Risk factor profile of cerebral small vessel disease and its subtypes.
        J Neurol Neurosurg Psychiatry. 2007; 78: 702-706
        • Vahedi K.
        • Kubis N.
        • Boukobza M.
        • Arnoult M.
        • Massin P.
        • Tournier-Lasserve E.
        • et al.
        COL4A1 mutation in a patient with sporadic, recurrent intracerebral hemorrhage.
        Stroke. 2007; 38: 1461-1464
        • Yoneda Y.
        • Haginoya K.
        • Kato M.
        • Osaka H.
        • Yokochi K.
        • Arai H.
        • et al.
        Phenotypic spectrum of COL4A1 mutations: porencephaly to schizencephaly.
        Ann Neurol. 2013; 73: 48-57