Expanding the phenotypic spectrum of RNASEH2B mutations: A new case of pure hereditary spastic paraplegia and a systematic review.

Background

Pathogenic variants in the RNASEH2B gene have been linked to Aicardi-Goutières syndrome type II (AGS-II), an early-onset encephalopathy that exhibits phenotypic overlaps with other neurodegenerative diseases, such as hereditary spastic paraplegia (HSP). A poor genotype-phenotype correlation, inconsistent findings in biomarker results of patients, and the challenge of distinguishing AGS-II from HSP underscore the necessity of performing comprehensive studies to address current difficulties in RNASEH2B-related cases. Here, through a detailed case report and comprehensive systematic review, we highlight clinical heterogeneity of RNASEH2B-related neurodegenerative cases and support the current view of considering RNASEH2B as an HSP-causing gene.

Methods

Using whole exome sequencing (WES), we identified an RNASEH2B variant, c.529G>A (p.Ala177Thr), in an Iranian patient suspected of having HSP, a mutation commonly reported in AGS-II. In contrast to AGS-II, clinical studies of the Iranian case were dominated by non-progressive HSP. A subsequent Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided review of RNASEH2B-related neurodegenerative disorders identified 49 relevant cases from 349 studies, revealing a variable spectrum of phenotypes.

Results

These phenotypes were classified into three overlapping categories: "RNASEH2B-related AGS", "atypical AGS-II", and "RNASEH2B-related HSP". 95 cases were diagnosed as RNASEH2B-related AGS or atypical AGS-II; six were classified as RNASEH2B-related HSP. One case was asymptomatic, and another involved intrauterine fetal death.

Conclusion

The current study highlights the expanding phenotypic spectrum of RNASEH2B mutations, emphasizing their potential to manifest as isolated pure HSP (pHSP) rather than classical AGS. This study underscores the importance of raising clinical awareness and incorporating genetic testing, particularly for atypical RNASEH2B cases.