ORPHA: 51; DO: 0050629;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q13.1 | Aicardi-Goutieres syndrome 3 | 610329 | Autosomal recessive | 3 | RNASEH2C | 610330 |
A number sign (#) is used with this entry because of evidence that Aicardi-Goutieres syndrome-3 (AGS3) is caused by homozygous mutation in the gene encoding subunit C of ribonuclease H2 (RNASEH2C; 610330) on chromosome 11q13.
Aicardi-Goutieres syndrome is an autosomal recessive disorder characterized by onset of encephalopathy in the first year of life following normal early development. Affected infants typically show extreme irritability, intermittent unexplained fever, chilblains, progressive microcephaly, spasticity, dystonia, and profound psychomotor retardation. Laboratory studies show lymphocytosis and raised titers of alpha-interferon in the cerebrospinal fluid. Brain imaging may show white matter abnormalities, intracerebral calcifications, and cerebral atrophy. Many patients die in childhood (summary by Vogt et al., 2013).
For a general phenotypic description and a discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).
Vogt et al. (2013) reported 2 Pakistani sisters who were variably affected with AGS3. The 12-month-old proband had severe infantile onset of disease, whereas her 4-year-old sister was intellectually normal and was only recognized to have the disorder after the diagnosis was made in her sister. The proband appeared vacant, with no social smile and poor visual fixation in the first months of life. Around 2 months of age, she showed poor head control, truncal hypotonia, and intermittent stiffening with jerky movements. Examination at age 1 year showed nystagmus, roving eye movements, hypotonia, dystonia, and brisk lower limb reflexes. Brain imaging showed delayed myelination, white matter abnormalities, and thinning of the corpus callosum. The older sister had only chilblains and a mild hemiplegia. Neither patient had calcifications in the basal ganglia.
Crow et al. (2006) performed genomewide linkage analysis on 6 consanguineous families with Aicardi-Goutieres syndrome and mapped the disease locus, which they termed AGS3, to a 4.9-cM interval on chromosome 11q13.2 between markers D11S4205 and D11S987 (maximum lod score of 4.54). Five of the families were Pakistani and 1 was Bangladeshi.
Crow et al. (2006) demonstrated that Aicardi-Goutieres syndrome-3 is an autosomal recessive disorder.
In affected members of 5 Pakistani families with AGS3, Crow et al. (2006) identified a homozygous mutation in the RNASEH2C gene (R69W; 610330.0001). Haplotype analysis suggested a founder effect. In affected members of a Bangladeshi family with AGS3, they identified a different homozygous mutation (K143I; 610330.0002) in the RNASEH2C gene.
In 2 Pakistani sisters with variable manifestations of AGS3, Vogt et al. (2013) identified homozygosity for the R69W mutation in the RNASEH2C gene. Both unaffected parents were heterozygous for the mutation.
Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., Ali, M., Semple, C., Aicardi, J., Babul-Hirji, R., Baumann, C., Baxter, P., and 33 others. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nature Genet. 38: 910-916, 2006. [PubMed: 16845400] [Full Text: https://doi.org/10.1038/ng1842]
Vogt, J., Agrawal, S., Ibrahim, Z., Southwood, T. R., Philip, S., MacPherson, L., Bhole, M. V., Crow, Y. J., Oley, C. Striking intrafamilial phenotypic variability in Aicardi-Goutieres syndrome associated with the recurrent Asian founder mutation in RNASEH2C. Am. J. Med. Genet. 161A: 338-342, 2013. [PubMed: 23322642] [Full Text: https://doi.org/10.1002/ajmg.a.35712]