title: Two families with novel missense mutations in COL4A1: When diagnosis can be missed.
abstract: 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.
authors: University of Torino, Department of Medical Sciences, Torino 10126, Italy.
authors: Elisa
authors: E
authors: Giorgio
authors: Città della Salute e della Scienza University Hospital, Department of Neuroscience, Torino 10126, Italy.
authors: Giovanna
authors: G
authors: Vaula
authors: Civil Hospital of Alba, Department of Neurology, Alba 12051, Italy.
authors: Giovanni
authors: G
authors: Bosco
authors: Città della Salute e della Scienza University Hospital, Department of Neuroscience, Torino 10126, Italy.
authors: Sara
authors: S
authors: Giacone
authors: University of Torino, Department of Medical Sciences, Torino 10126, Italy.
authors: Cecilia
authors: C
authors: Mancini
authors: University of Torino, Department of Medical Sciences, Torino 10126, Italy.
authors: Alessandro
authors: A
authors: Calcia
authors: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Torino 10126, Italy.
authors: Simona
authors: S
authors: Cavalieri
authors: Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Torino 10126, Italy.
authors: Eleonora
authors: E
authors: Di Gregorio
authors: Cottolengo Hospital, Ophthalmology Unit, Torino 10152, Italy.
authors: Roberta
authors: R
authors: Rigault De Longrais
authors: Città della Salute e della Scienza University Hospital, Department of Neuroscience, Torino 10126, Italy.
authors: Sabrina
authors: S
authors: Leombruni
authors: Città della Salute e della Scienza University Hospital, Department of Neuroscience, Torino 10126, Italy; University of Torino, Department of Neuroscience, Torino 10126, Italy.
authors: Lorenzo
authors: L
authors: Pinessi
authors: Città della Salute e della Scienza University Hospital, Department of Neuroscience, Torino 10126, Italy.
authors: Paolo
authors: P
authors: Cerrato
authors: University of Torino, Department of Medical Sciences, Torino 10126, Italy; Città della Salute e della Scienza University Hospital, Medical Genetics Unit, Torino 10126, Italy. Electronic address: alfredo.brusco@unito.it.
authors: Alfredo
authors: A
authors: Brusco
authors: University of Torino, Department of Medical Sciences, Torino 10126, Italy.
authors: Alessandro
authors: A
authors: Brussino
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology*; D024141:Collagen Type IV / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D007558:Italy; D056784:Leukoencephalopathies / Q000235:genetics* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D000068079:Motor Disorders / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense; D010375:Pedigree; D065708:Porencephaly; D011247:Pregnancy; D012161:Retinal Artery / Q000002:abnormalities / Q000503:physiopathology; D012166:Retinal Hemorrhage / Q000235:genetics / Q000503:physiopathology; D013036:Spasms, Infantile / Q000235:genetics / Q000503:physiopathology
chemical_list: C547475:COL4A1 protein, human; D024141:Collagen Type IV
keywords: COL4A1; COL4A2; Fetal porencephaly; Hereditary angiopathy with nephropathy, aneurysms and muscle cramp (HANAC) syndrome; Porencephaly; Variable expressivity