RNASEH2A – Aicardi-Goutieres syndrome

The RNASEH2A gene encodes the catalytic subunit of the RNase H2 endonuclease complex, essential for removal of ribonucleotides from genomic DNA. Pathogenic variants in RNASEH2A cause autosomal recessive Aicardi-Goutieres syndrome, a type I interferonopathy characterized by early-onset encephalopathy, intracranial calcifications, and systemic inflammation. AGS exhibits locus heterogeneity with seven genes, including RNASEH2A (AGS1). Clinical manifestations often mimic congenital viral infections, complicating early diagnosis. Genetic confirmation via biallelic RNASEH2A variants informs prognosis and management. Here, we summarise evidence supporting a definitive gene–disease relationship.

Biallelic RNASEH2A variants have been reported in at least 10 unrelated probands across four cohorts ([PMID:17846997],[PMID:35551623],[PMID:29239743],[PMID:37456470]). These include missense, synonymous splice site, and canonical splice donor mutations. In the initial mutation screen of 127 pedigrees, 3 families harboured RNASEH2A variants in a total of 3 probands ([PMID:17846997]). Subsequent population studies identified a single AGS4 case in a Chinese cohort of 23 ([PMID:35551623]) and five RNASEH2A-positive cases in an Arab series (20.8% of 24) ([PMID:29239743]). A novel homozygous splice-site variant c.549+1G>T was also reported in an Indian individual ([PMID:37456470]). Collectively, these data provide robust case-level evidence.

All RNASEH2A-associated AGS cases follow an autosomal recessive inheritance pattern, with biallelic variant segregation in affected individuals. In the 2007 pedigree series, variants segregated with disease status across three families ([PMID:17846997]). Although detailed segregation counts are limited, additional affected relatives have been reported, yielding segregation evidence in multiple kindreds. No dominant-negative or heterozygous de novo RNASEH2A variants have been implicated. The consistent recessive inheritance underscores the requirement for biallelic loss-of-function or hypomorphic alleles. These segregation data reinforce a causal relationship.

RNASEH2A variants encompass predominantly missense and splice-site mutations. Among the missense alleles, c.635A>T (p.Asn212Ile) and c.872G>A (p.Arg291His) are recurrent in unrelated families ([PMID:17846997],[PMID:31529068]). Synonymous variants c.69G>A (p.Val23Val) and c.75C>T (p.Arg25Arg) create cryptic splice sites, leading to exon deletions and loss of enzymatic activity ([PMID:23592335]). The novel Indian c.549+1G>T splice donor variant further expands the splicing defect spectrum. No founder RNASEH2A alleles have been described to date. Allele frequencies in gnomAD confirm rarity consistent with AGS prevalence.

In vitro studies demonstrate that RNASEH2A pathogenic alleles impair RNase H2 function. Synonymous splice-site variants cause aberrant exon skipping, reduce protein levels, and abrogate catalytic activity ([PMID:23592335]). Recombinant RNase H2 A-Gly37Ser variant retains only 0.3–1% activity, while R291H and N212I mutants exhibit compromised heterotrimer stability ([PMID:31529068]). Protein structural modeling and cellular assays corroborate these findings, linking enzymatic deficits to accumulation of ribonucleotides and activation of the interferon response. These experimental data deliver functional concordance with the human phenotype, consistent with haploinsufficiency and loss-of-function mechanisms. No rescue experiments have been reported to date.

Collectively, the convergence of genetic, segregation, and functional data establishes a definitive gene–disease association between biallelic RNASEH2A variants and AGS1. Clinical genetic testing should include RNASEH2A sequencing and splicing assays when AGS is suspected. Recognizing RNASEH2A-mediated AGS facilitates early interferonopathy management and informs family planning. Further studies may elucidate genotype–phenotype correlations and potential therapeutic targets in the DNA repair pathway. Additional evidence from patient-derived models and rescue studies could enrich mechanistic insights but does not alter current clinical validity. Key Take-home: RNASEH2A biallelic variants are a definitive cause of autosomal recessive Aicardi-Goutieres syndrome, supporting diagnostic testing and tailored interventions.

References

• American Journal of Human Genetics • 2007 • Clinical and molecular phenotype of Aicardi-Goutieres syndrome PMID:17846997
• Human Mutation • 2013 • Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutieres syndrome PMID:23592335
• Pediatric Neurology • 2018 • Phenotypic and Molecular Spectrum of Aicardi-Goutieres Syndrome: A Study of 24 Patients PMID:29239743
• Journal of Biochemistry • 2019 • Characterization of six recombinant human RNase H2 bearing Aicardi-Goutieres syndrome causing mutations PMID:31529068
• World Journal of Pediatrics • 2022 • Analysis of clinical characteristics of children with Aicardi-Goutieres syndrome in China PMID:35551623
• Cureus • 2023 • In Silico Characterization of RNASEH2A Pathogenic Variants and Identification of Novel Splice Site Donor Variant c.549+1G>T in Indian Population PMID:37456470

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