Submission Details

RNASEH2B-related Type 1 Interferonopathy, Autosomal Recessive

RNASEH2B was first reported in relation to autosomal recessive Aicardi-Goutieres syndrome type 2 (OMIM: 610326) in 2006 (PMID: 16845400). RNASEH2B encodes the ribonuclease H2 subunit B, which comprises 308 amino acids. RNASEH enzymes endolytically cleave ribonucleotides from RNA:DNA duplexes, which occur during DNA replication, transcription and translation. RNASEH2 has been proposed to function in the removal of lagging strand Okazaki fragment RNA primers during DNA replication, as well as in the excision of single ribonucleotides from RNA:DNA duplexes (PMIDs: 21177854, 16845400).

The described autosomal recessive RNASEH2B phenotype is considered to be a form of type 1 interferonopathy, which is defined as a condition in which increased type 1 interferon signaling leads to autoimmune and neurological disorders (MONDO: 0700257). These disorders are caused by variants in genes involved in nucleic acid metabolism, sensing, and the innate immune response. Individuals with biallelic variants in RNASEH2B can present with a range of symptoms of variable severity and age of onset, within the context of an autoimmune disease.

At least 10 unique variants (missense, splicing, nonsense) have been reported across 13 probands in 6 publications (PMIDs: 33981319, 33307271, 36775013, 22882256, 39183359, 25604658) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is thought to be loss of function. This gene-disease relationship is also supported by experimental evidence (model system studies, PMIDs: 34655526, 26903602). A study by Aditi et al., 2021 generated a murine model of neural Rnaseh2b inactivation (Rnaseh2bNes-cre), which demonstrated cerebellar atrophy, loss of granule neurons and interneurons, thinning of the corpus callosum, loss of oligodendrocytes, and white matter abnormalities. A study by Mackenzie et al., 2016 generated a murine model by knock-in of the A174T missense variant (c.520A>G) into exon 7 of Rnaseh2b in mouse embryonic stem cells, which demonstrated reduced cellular levels of all three RNase H2 subunits and demonstrated significant interferon-stimulated gene (ISG) transcript upregulation that recapitulated the ISG signature observed in RNase H2 AGS patients.

In summary, there is definitive evidence supporting the relationship between RNASEH2B and autosomal recessive RNASEH2B-related type 1 interferonopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date November 20, 2024 (SOP Version 11).