{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T01:26:44Z","timestamp":1787794004603,"version":"build-2784847793"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pediatr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Aicardi-Gouti\u00e8res syndrome type 5 (AGS5) is a rare pediatric-onset monogenic interferonopathy caused by loss-of-function variants in the\n                      <jats:italic>SAMHD1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>SAMHD1<\/jats:italic>\n                      (NM_015474): c.1503\u2009+\u20091G\u2009&amp;gt;\u2009A, 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This report expands the mutational and phenotypic spectrum of\n                      <jats:italic>SAMHD1<\/jats:italic>\n                      -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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fped.2026.1787581","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:42:26Z","timestamp":1778823746000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A homozygous splice-site variant in SAMHD1 shows variable expressivity of Aicardi-Gouti\u00e8res syndrome type 5: a case report and literature review"],"prefix":"10.3389","volume":"14","author":[{"given":"Hammad","family":"Yousaf","sequence":"first","affiliation":[{"name":"Department of Biological and Biomedical Sciences, The Aga Khan 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