Striking intrafamilial phenotypic variability in Aicardi-Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C

Julie Vogt, Shakti Agrawal, Zala Ibrahim, Taunton R. Southwood, Sunny Philip, Lesley Macpherson, Malini V. Bhole, Yanick J. Crow, Christine Oley

    Research output: Contribution to journalArticlepeer-review

    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.
    Original languageEnglish
    Pages (from-to)338-342
    Number of pages4
    JournalAmerican Journal of Medical Genetics, Part A
    Volume161
    Issue number2
    DOIs
    Publication statusPublished - Feb 2013

    Keywords

    • Aicardi-Goutières syndrome
    • Chilblains
    • RNASEH2C

    Fingerprint

    Dive into the research topics of 'Striking intrafamilial phenotypic variability in Aicardi-Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C'. Together they form a unique fingerprint.

    Cite this