Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutières syndrome

Marco L Leung, Whitney Woodhull, Carolina Uggenti, Shauna Schord, Raul Perez Mato, Diana P Rodriguez, Margie Ream, Yanick J Crow*, Mari Mori

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Aicardi-Goutières syndrome (AGS) is a progressive multisystem disorder including encephalopathy with significant impacts on intellectual and physical abilities. An early diagnosis is becoming ever more crucial, as targeted therapies are emerging. A deep understanding of the molecular heterogeneity of AGS can help guide the early diagnosis and clinical management of patients, and inform recurrence risks. Here, we detail the diagnostic odyssey of a patient with an early presentation of AGS. Exome and genome sequencing detected an intronic RNASEH2B variant missed in a conventional leukodystrophy NGS gene panel. RNA studies demonstrated that a c.322-17 A > G variant affected splicing and caused 16-nucleotide intronic retention in the RNASEH2B transcript, introducing an out-of-frame early termination codon. RNASEH2B expression in the patient's blood was reduced when compared to controls. Our study highlights the pathogenicity of this intronic variant and the importance of its inclusion in variant assessment.

Original languageEnglish
Pages (from-to)104731
JournalEuropean journal of medical genetics
Issue number4
Early online date11 Feb 2023
Publication statusPublished - Apr 2023

Keywords / Materials (for Non-textual outputs)

  • Autoimmune Diseases of the Nervous System/genetics
  • Exome
  • Humans
  • Mutation
  • Nervous System Malformations/genetics


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