RNASEH2B – Aicardi–Goutieres syndrome type 2

RNASEH2B encodes the B subunit of the RNase H2 complex, essential for ribonucleotide excision repair. Biallelic loss-of-function variants in RNASEH2B cause Aicardi–Goutieres syndrome type 2 (AGS2), a type I interferonopathy characterized by early-onset encephalopathy and progressive neurological decline (PMID:17846997).

Inheritance is autosomal recessive, with over 47 families (PMID:17846997) and >100 affected individuals (PMID:29239743) reported. Segregation analysis in multiple sibships further confirms pathogenicity.

The RNASEH2B variant spectrum includes missense (e.g., c.529G>A (p.Ala177Thr)), splice-site (c.322-3C>G), nonsense, and frameshift alleles. A founder splice mutation c.322-3C>G is enriched in the Faroe Islands (PMID:22882256).

Case reports describe two siblings homozygous for c.529G>A (p.Ala177Thr) presenting with spastic quadriplegia and anarthria but preserved intellect and atypical basal ganglia iron accumulation (PMID:28762473), and two sisters with homozygous c.554T>G (p.Val185Gly) exhibiting intracranial calcifications, seizures, chilblains, microcephaly, and spasticity (PMID:28332073).

Functional assays on recombinant RNase H2 complexes show that B subunit missense variants reduce thermal stability and, in some cases, enzymatic activity (p.Val185Gly retains ~50–120% activity but diminished stability) (PMID:31529068). Mechanistically, RNASEH2B mutations impair ribonucleotide removal, provoking interferon-mediated neuroinflammation.

Clinical features span progressive microcephaly (HP:0000253), microcephaly (HP:0000252), spasticity (HP:0001257), seizures (HP:0001250), cognitive impairment (HP:0100543), and anarthria (HP:0002425). Phenotypes range from severe neonatal presentations to later-onset forms with preserved cognitive function.

No conflicting reports dispute the autosomal recessive association of RNASEH2B with AGS. Population allele frequencies are consistent with rare, pathogenic variants.

Integrating extensive genetic and experimental data supports a definitive gene–disease relationship. Key take-home: RNASEH2B genetic testing is essential for early diagnosis, management, and genetic counseling in patients with unexplained interferonopathy and neurodevelopmental regression.

References

• American journal of human genetics • 2007 • Clinical and molecular phenotype of Aicardi-Goutieres syndrome PMID:17846997
• Acta paediatrica (Oslo, Norway : 1992) • 2012 • A novel RNASEH2B splice site mutation responsible for Aicardi-Goutieres syndrome in the Faroe Islands PMID:22882256
• Developmental medicine and child neurology • 2017 • Late diagnosis and atypical brain imaging of Aicardi–Goutieres syndrome: are we failing to diagnose Aicardi–Goutieres syndrome PMID:28762473
• Metabolic brain disease • 2017 • Aicardi–Goutieres syndrome: unusual neuro-radiological manifestations PMID:28332073
• 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
• European journal of medical genetics • 2023 • Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi–Goutieres syndrome PMID:36775013

Evidence Based Scoring (AI generated)