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

doi:10.1016/j.ejmg.2023.104731

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

Eur J Med Genet. 2023 Apr;66(4):104731. doi: 10.1016/j.ejmg.2023.104731. Epub 2023 Feb 11.

Authors

Marco L Leung¹, Whitney Woodhull², Carolina Uggenti³, Shauna Schord⁴, Raul Perez Mato³, Diana P Rodriguez⁵, Margie Ream⁶, Yanick J Crow⁷, Mari Mori⁸

Affiliations

¹ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Departments of Pathology, Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA. Electronic address: marco.leung@nationwidechildrens.org.
² Division of Pediatric Neurology, Renown Children's Hospital, Reno, NV, USA; University of Nevada, Reno School of Medicine, Reno, NV, USA.
³ MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK.
⁴ Division of Hospital Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
⁵ Department of Radiology, Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University College of Medicine, Columbus, OH, 43210, USA.
⁶ The Ohio State University College of Medicine, Columbus, OH, 43210, USA; Division of Pediatric Neurology, Nationwide Children's Hospital, Columbus, OH, USA.
⁷ MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK; Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Université de Paris, Paris, France.
⁸ The Ohio State University College of Medicine, Columbus, OH, 43210, USA; Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Electronic address: mari.mori@nationwidechildrens.org.

PMID: 36775013
DOI: 10.1016/j.ejmg.2023.104731

Abstract

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.

Keywords: Aicardi-Goutières syndrome; Leukodystrophy; RNASEH2B; RNase H2; Splicing variant.

MeSH terms

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

Supplementary concepts

Aicardi-Goutieres syndrome