Striking intrafamilial phenotypic variability in Aicardi–Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C |
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Authors: | Julie Vogt Shakti Agrawal Zala Ibrahim Taunton R. Southwood Sunny Philip Lesley MacPherson Malini V. Bhole Yanick J. Crow Christine Oley |
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Affiliation: | 1. Centre for Rare Diseases and Personalised Medicine, Department of Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK;2. West Midlands Regional Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK;3. Department of Paediatric Neurology, Birmingham Children's Hospital, Birmingham, UK;4. Department of Paediatrics, Russells Hall Hospital, Dudley, West Midlands, UK;5. Department of Paediatric Rheumatology, Birmingham Children's Hospital, Birmingham, UK;6. Department of Paediatric Radiology, Birmingham Children's Hospital, Birmingham, UK;7. Department of Immunology, Russells Hall Hospital, Dudley, West Midlands, UK;8. Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, UK |
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Abstract: | Aicardi–Goutières syndrome (AGS) is an encephalopathy of early childhood which is most commonly inherited as an autosomal recessive trait. The disorder demonstrates significant genetic heterogeneity with causative mutations in five genes identified to date. Although most patients with AGS experience a severe neonatal or infantile presentation, poor neurodevelopmental outcome and reduced survival, clinical variability in the onset and severity of the condition is being increasingly recognized. A later presentation with a more variable effect on development, morbidity and mortality has been particularly observed in association with mutations in SAMHD1 and RNASEH2B. In contrast, the recurrent c.205C > T (p.R69W) RNASEH2C Asian founder mutation has previously only been identified in children with a severe AGS phenotype. Here, to our knowledge, we present the first report of marked phenotypic variability in siblings both harboring this founder mutation in the homozygous state. In this family, one female child had a severe AGS phenotype with an onset in infancy and profound developmental delay, whilst an older sister was of completely normal intellect with a normal head circumference and was only diagnosed because of the presence of chilblains and a mild hemiplegia. An appreciation of intrafamilial phenotypic expression is important in the counseling of families considering prenatal diagnosis, and may also be relevant to the assessment of efficacy in future clinical trials. In addition, marked phenotypic variation raises the possibility that more mildly affected patients are not currently identified. © 2013 Wiley Periodicals, Inc. |
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Keywords: | Aicardi– Goutiè res syndrome chilblains RNASEH2C |
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