Further refinement of COL4A1 and COL4A2 related cortical malformations

• Published in: European journal of medical genetics Vol. 61; no. 12; pp. 765 - 772
• Main Authors: Cavallin, Mara, Mine, Manuele, Philbert, Marion, Boddaert, Nathalie, Lepage, Jean Marie, Coste, Thibault, Lopez-Gonzalez, Vanessa, Sanchez-Soler, Maria Jose, Ballesta-Martínez, Maria Juliana, Remerand, Ganaëlle, Pasquier, Laurent, Guët, Agnès, Chelly, Jamel, Lascelles, Karine, Prieto-Morin, Carol, Kossorotoff, Manoelle, Tournier Lasserve, Elisabeth, Bahi-Buisson, Nadia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.12.2018
• Subjects: Child; Child, Preschool; COL4A1/A2; Collagen Type IV - genetics; Cortical malformations; Female; Genetics; Humans; Infant; Life Sciences; Magnetic Resonance Imaging; Male; Mutation; Polymicrogyria; Polymicrogyria - diagnostic imaging; Polymicrogyria - genetics; Polymicrogyria - physiopathology; Porencephaly - diagnostic imaging; Porencephaly - genetics; Porencephaly - physiopathology; Schizencephaly; Schizencephaly - diagnostic imaging; Schizencephaly - genetics; Schizencephaly - physiopathology; Subcortical heterotopia; Schizencephaly; Polymicrogyria; COL4A1/A2; Cortical malformations; Subcortical heterotopia
• ISSN: 1769-7212; 1878-0849; 1878-0849
• DOI: 10.1016/j.ejmg.2018.10.004

Mutations in COL4A1 have been reported in schizencephaly and porencephaly combined with microbleeds or calcifications, often associated with ocular and renal abnormalities, myopathy, elevated creatine kinase levels and haemolytic anaemia. In this study, we aimed to clarify the phenotypic spectrum of COL4A1/A2 mutations in the context of cortical malformations that include schizencephaly, polymicrogyria and/or heterotopia. We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event. These included 6 cases with asymmetrical or unilateral schizencephaly and/or polymicrogyria and 3 cases with bilateral schizencephaly. One de novo missense COL4A1 mutation (c.3715 G > A, p.(Gly1239Arg)) and two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A). In three other cases, COL4A1 variants of unknown significance were identified. None of our patients demonstrated neuromuscular or hematological anomalies. Brain malformations included a combination of schizencephaly, mainly asymmetrical, with porencephaly or ventriculomegaly (3/3 mutated patients). We did not observe microbleeds or microcalcifications in any of our cases, hence we do not believe that they represent a distinctive feature of COL4A1/A2 mutations. Our study further emphasizes the need to search for both COL4A1 and COL4A2 mutations in children presenting with uni- or bilateral polymicrogyria with schizencephaly, even in the absence of intracranial microbleeds, calcification or associated systemic features.