A novel RNASEH2B splice site mutation responsible for Aicardi-Goutieres syndrome in the Faroe Islands

Acta Pediatrica, 08/16/2012

Ostergaard E et al. – The previously identified RNASEH2B mutations comprise altogether 20 mutations (missense, nonsense and splice site) with all patients harboring at least one missense mutation. The severe phenotype of the Faroese patients compared to the previously reported patients with RNASEH2B mutations may be caused by the presence of two null alleles (although some residual normal splicing cannot be ruled out), whereas patients with one or two missense mutations may have some, albeit abnormal RNASEH2B protein, and hence some residual activity of RNASEH2B, explaining their milder phenotype.

Methods

  • A genome-wide search for homozygosity revealed one single 15.6 Mb region of homozygosity on chromosome 13, which included RNASEH2B, where a splice site mutation, c.322-3C>G was identified.
  • Screening of 170 anonymous Faroese controls revealed a carrier frequency of approx. 1.8%, corresponding to an incidence of AGS in the Faroe Islands of around 1 in 12,300.

Results

  • The previously identified RNASEH2B mutations comprise altogether 20 mutations (missense, nonsense and splice site) with all patients harboring at least one missense mutation.
  • The severe phenotype of the Faroese patients compared to the previously reported patients with RNASEH2B mutations may be caused by the presence of two null alleles (although some residual normal splicing cannot be ruled out), whereas patients with one or two missense mutations may have some, albeit abnormal RNASEH2B protein, and hence some residual activity of RNASEH2B, explaining their milder phenotype.

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