RNASEH2C – Aicardi-Goutieres Syndrome

RNASEH2C encodes the C subunit of the heterotrimeric RNase H2 complex responsible for removal of ribonucleotides embedded in DNA. Biallelic mutations in RNASEH2C cause Aicardi-Goutieres syndrome (AGS), a type I interferonopathy presenting as an early-onset encephalopathy with intracranial calcification, leukodystrophy, and progressive neurologic deficits (PMID:17846997).

Autosomal recessive RNASEH2C variants have been identified in 18 unrelated families, establishing its role in AGS3 (PMID:17846997). Most pathogenic alleles are missense changes affecting conserved residues, with rare splice and truncating variants reported.

The c.205C>T (p.Arg69Trp) founder variant is recurrent in Asian populations, first described in severe neonatal cases and later observed with marked intrafamilial phenotypic variability in siblings (PMID:23322642). It has been independently confirmed as a founder allele in three Indian families (PMID:29150899) and identified in two patients from a 24-individual Arab cohort (8.3% of cases) (PMID:29239743).

A novel Chinese-specific founder mutation, c.194G>A (p.Gly65Asp), was detected homozygously in three unrelated patients, further extending the spectrum of RNASEH2C missense alleles (PMID:37092250). In a Chinese multi-center study, three AGS3 cases (13% of AGS1-3 cohort) harbored RNASEH2C variants, affirming its contribution across populations (PMID:35551623).

Segregation studies demonstrate homozygous inheritance of these founder variants in affected sibships (two siblings in one family, three Indian families), supporting their pathogenicity and enabling genetic counseling (PMID:23322642; PMID:29150899).

Functional assays of recombinant RNase H2 complexes reveal that the p.Arg69Trp variant retains near-normal endonuclease activity but exhibits reduced thermal stability (~3 °C lower melting temperature), consistent with a destabilizing mechanism of partial loss-of-function (PMID:31529068).

Collectively, the extensive case series, recurrence of founder alleles, segregation in multiple families, and concordant biochemical data constitute definitive evidence for RNASEH2C as a causative gene in AGS3. Biallelic RNASEH2C testing is recommended for diagnosis, carrier screening, and guiding prenatal counseling.

References

• American Journal of Human Genetics • 2007 • Clinical and molecular phenotype of Aicardi-Goutieres syndrome. PMID:17846997
• American Journal of Medical Genetics Part A • 2013 • Striking intrafamilial phenotypic variability in Aicardi-Goutieres syndrome associated with the recurrent Asian founder mutation in RNASEH2C PMID:23322642
• American Journal of Medical Genetics Part A • 2018 • p.Arg69Trp in RNASEH2C is a founder variant in three Indian families with Aicardi-Goutieres syndrome PMID:29150899
• Pediatric Neurology • 2018 • Phenotypic and Molecular Spectrum of Aicardi-Goutieres Syndrome: A Study of 24 Patients PMID:29239743
• World Journal of Pediatrics • 2022 • Analysis of clinical characteristics of children with Aicardi-Goutieres syndrome in China. PMID:35551623
• Journal of Biochemistry • 2019 • Characterization of six recombinant human RNase H2 bearing Aicardi-Goutieres syndrome causing mutations PMID:31529068
• Clinical Genetics • 2023 • RNASEH2C c.194G>A is a Chinese-specific founder mutation in three unrelated patients with Aicardi-Goutieres syndrome 3 PMID:37092250

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