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: Elisa Giorgio, Giovanna Vaula, Giovanni Bosco, Sara Giacone, Cecilia Mancini, Alessandro Calcia, Simona Cavalieri, Eleonora Di Gregorio, Roberta Rigault De Longrais, Sabrina Leombruni, Lorenzo Pinessi, Paolo Cerrato, Alfredo Brusco, Alessandro Brussino
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 352 Issue 1-2 Pg. 99-104 (May 15 2015) ISSN: 1878-5883 [Electronic] Netherlands
• PMID: 25873210 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• COL4A1 protein, human
• Collagen Type IV

Topics

• Adolescent
• Adult
• Brain (pathology)
• Collagen Type IV (genetics)
• Family
• Female
• Humans
• Italy
• Leukoencephalopathies (genetics, physiopathology)
• Magnetic Resonance Imaging
• Male
• Motor Disorders (genetics, physiopathology)
• Mutation, Missense
• Pedigree
• Porencephaly
• Pregnancy
• Retinal Artery (abnormalities, physiopathology)
• Retinal Hemorrhage (genetics, physiopathology)
• Spasms, Infantile (genetics, physiopathology)