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

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.