Clinical Report: Homozygous Splice-Site Variant in SAMHD1 in AGS5

Overview

This report describes a consanguineous family with two siblings affected by Aicardi-Goutières syndrome type 5 (AGS5) due to a homozygous splice-site variant in the SAMHD1 gene. The findings highlight the phenotypic variability associated with AGS5, emphasizing the need for awareness of this condition in pediatric patients with neurodevelopmental delays.

Background

Aicardi-Goutières syndrome type 5 (AGS5) is a rare genetic disorder characterized by early-onset neurodevelopmental impairment and is linked to mutations in the SAMHD1 gene. Understanding the clinical presentation and genetic underpinnings of AGS5 is crucial for accurate diagnosis and management, particularly given its phenotypic heterogeneity. This case underscores the importance of genetic testing in children with unexplained neurodevelopmental issues.

Data Highlights

Whole-exome sequencing identified a homozygous canonical splice donor site variant in SAMHD1 (c.1503+1G>A), classified as pathogenic. The affected siblings exhibited early-infantile-onset neurodevelopmental delay, microcephaly, and muscular atrophy, but lacked common features such as spasticity and seizures.

Key Findings

• The siblings presented with significant neurodevelopmental delays and microcephaly.
• Neuroimaging did not show typical findings associated with AGS5, such as intracranial calcifications.
• The identified SAMHD1 variant is predicted to disrupt normal splicing, leading to loss of function.
• Both parents were heterozygous carriers, confirming an autosomal recessive inheritance pattern.
• This case expands the known mutational spectrum of AGS5 and highlights its variable expressivity.

Clinical Implications

Clinicians should consider Aicardi-Goutières syndrome in pediatric patients presenting with unexplained neurodevelopmental delays, even in the absence of classic features. Genetic testing for SAMHD1 variants may be warranted to confirm diagnosis and guide management.

Conclusion

This case report emphasizes the importance of recognizing the diverse clinical manifestations of AGS5 and the role of genetic testing in establishing a diagnosis. Further research is needed to elucidate the full spectrum of phenotypic variability associated with SAMHD1 mutations.

Related Resources & Content

1. Acta Neuropathologica, 2023 -- Dysfunction of AMFR Leads to Autosomal Recessive Spastic Paraplegia in Humans, Potentially Treatable with Statins in Preclinical Studies
2. Frontiers in Cardiovascular Medicine, 2026 -- Case Report: A typical triad of Danon disease caused by a LAMP2 splice-donor variant with multilevel functional validation
3. Frontiers in Endocrinology, 2026 -- Molecular impact of a novel HNF1B missense variant in childhood-onset MODY5: a case report and functional study
4. French protocol for diagnosis and management of type 1 interferonopathies - ScienceDirect, 2025
5. Acta Neuropathologica — Exploring the Connection Between G51D SNCA Mutation and α-Synucleinopathy: Implications for Parkinson's Disease and Multiple System Atrophy
6. French protocol for diagnosis and management of type 1 interferonopathies
7. Efficacy of JAK1/2 inhibitors in AGS genes-related interferonopathies: A multicenter retrospective observational study with treated vs untreated comparison - PubMed