New Phenotypes Associated With Pathogenic RNASEH2B and SAMHD1 Variants

Area of Science:

• Genetics
• Immunology
• Neurology

Background:

• Aicardi-Goutières syndrome (AGS) is a genetic disorder of the innate immune response, primarily linked to pathogenic variants in nine genes (AGS1-9).
• These variants typically cause a spectrum of neurological and developmental issues, but rare extra-neurologic presentations have also been reported.
• The precise mechanisms linking these genetic variants to diverse clinical manifestations are still being elucidated.

Purpose of the Study:

• To report two new cases of Aicardi-Goutières syndrome with homozygous pathogenic variants in RNASEH2B and SAMHD1.
• To describe novel extra-neurologic manifestations and a unique association with idiopathic hypoparathyroidism in a patient with SAMHD1 variants.
• To expand the understanding of the phenotypic spectrum associated with AGS genes, particularly focusing on extra-neurologic symptoms.

Main Methods:

• Case report of two patients with homozygous pathogenic variants in RNASEH2B and SAMHD1.
• Clinical phenotyping including neurological examination, imaging, and biochemical tests.
• Literature review to summarize extra-neurologic manifestations of AGS genes-related disorders.

Main Results:

• Patient 1 with RNASEH2B variant presented with arthropathy, livedo reticularis, intermittent fever, and hepatosplenomegaly.
• Patient 2 with SAMHD1 variant exhibited late-onset muscle spasms, impaired calcium/phosphorus homeostasis, intracranial calcification, and chilblains, alongside average intelligence.
• This study reports the first association between idiopathic hypoparathyroidism and a pathogenic SAMHD1 variant, broadening the known phenotype.

Conclusions:

• Pathogenic variants in AGS genes can lead to a wider range of extra-neurologic symptoms than previously recognized.
• The identification of idiopathic hypoparathyroidism in a patient with SAMHD1 variants expands the clinical spectrum of this gene.
• Improved understanding of these phenotypes facilitates earlier diagnosis, genetic counseling, and targeted health surveillance for affected individuals.