A homozygous splice-site variant in SAMHD1 shows variable expressivity of Aicardi-Goutières syndrome type 5: A case report and literature review

Authors

• Hammad Yousaf, Aga Khan UniversityFollow
• Zehra Zonash, Aga Khan UniversityFollow
• Javeria Manzoor, Aga Khan UniversityFollow
• Asmat Ali, Aga Khan UniversityFollow
• Lubaba Binte Khalid, Aga Khan UniversityFollow
• Ghazala Zafar, Aga Khan UniversityFollow
• Sajid Ali, Aga Khan University
• Mathias Toft, University of Oslo
• Ambrin Fatima, Aga Khan UniversityFollow
• Zafar Iqbal, Oslo University Hospital

Document Type

Case Report

Department

Medical College Pakistan; Centre for Regenerative Medicine and Stem Cell Research

Abstract

Background: Aicardi-Goutières syndrome type 5 (AGS5) is a rare pediatric-onset monogenic interferonopathy caused by loss-of-function variants in the SAMHD1 gene. Affected individuals typically present in infancy with microcephaly, leukodystrophy, intracranial calcifications, developmental delay, and spasticity. However, phenotypic heterogeneity and atypical systemic manifestations have been increasingly recognized.
Case presentation: We report a consanguineous Pakistani family with two siblings affected by AGS5. The affected individuals (9-year-old female and 7-year-old male) presented early-infantile-onset neurodevelopmental delay, microcephaly, dysarthria, bilateral lower-limb muscular atrophy, and mild planovalgus deformity. They never attained independent ambulation and had only rudimentary speech. Notably, neuroimaging findings, spasticity, seizures, and aggressive behavior were absent. Whole-exome sequencing identified a homozygous canonical splice donor site variant in SAMHD1 (NM_015474): c.1503 + 1G > A, predicted to abolish normal splicing and classified as pathogenic by the ACMG criteria (i.e., PVS1, PM2, PP1). Segregation analysis confirmed an autosomal recessive mode of inheritance, with both parents being heterozygous carriers and affected individuals homozygous for the variant.
Conclusion: This report expands the mutational and phenotypic spectrum of SAMHD1-related AGS. The identification of a homozygous canonical splice donor site variant in a consanguineous South Asian family underscores the importance of considering AGS in children with congenital microcephaly and progressive neurodevelopmental impairment, even in the absence of intracerebral findings, chilblains, and spasticity.

Comments

Volume, and issue are not provided by the author/publisher.

Publication (Name of Journal)

Frontiers in Pediatrics

DOI

10.3389/fped.2026.1787581

Recommended Citation

Yousaf, H., Zonash, Z., Manzoor, J., Ali, A., Khalid, L. B., Zafar, G., Ali, S., Toft, M., Fatima, A., Iqbal, Z. (2026). A homozygous splice-site variant in SAMHD1 shows variable expressivity of Aicardi-Goutières syndrome type 5: A case report and literature review. Frontiers in Pediatrics, 1-11.
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_bbs/1118