case_images: PMC11791129_01
case_images: Family pedigree and patient presentation. A, Pedigree chart illustrating inheritance pattern of SAMHD1 deletion. Carriers marked with central circle (carrier status of II.3 is unknown). Patient indicated with black arrow. B, Chilblain-like skin lesions observed on the patient's feet and hands. C, Computed tomography scan showing ependymal calcifications in the lateral ventricles. D, Integrated Genome Viewer visualization of SAMHD1 exons 1 to 3 in the patient (II.1), father (I.1), mother (I.2), and healthy control (HC).
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case_images: PMC11791129_01_gr1.jpg
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case_images: We present the case of a 33-year-old man who was born to nonconsanguineous Ashkenazi Jewish parents and has 1 healthy brother (Fig 1, A). Ependymal calcifications were identified in the lateral ventricles by using a computed tomography scan when the patient was 13.5 years old (Fig 1, C). The copy number variation (CNV)-calling algorithm Atlas-CNV identified a homozygous deletion encompassing exon 1 of SAMHD1 in the patient and heterozygous deletions in the parents (see Fig E1, A in the Online Repository at www.jaci-global.org). The deletion was visually confirmed using Integrated Genome Viewer (Fig 1, D). PCR with primer flanking the deleted region generated an approximately 500-bp product only in the patient and his carrier parents but not in the patient's healthy brother or a healthy control sample (Fig 2, A and see Fig E1, B). This deletion is the most frequent pathogenic variant causing SAMHD1-associated AGS in the Ashkenazi Jewish population. The deletion is likely caused through nonallelic homologous recombination mediated by 2 highly homologous (83% sequence identity) Alu elements flanking the deleted region (see Fig E1, C).
case_images: Genetic analysis and expression profiling of SAMHD1. A, PCR amplification of SAMHD1 fragment from genomic DNA of family members and healthy control (HC). An approximately 500-bp PCR product is generated in the patient and carrier parents but not in the patient's brother or HC. B, Sanger sequencing of PCR fragment shows breakpoints of deletion. C, Normalized expression of SAMHD1 and ISG15 in the family and HC. D, NanoString analysis of interferon-stimulated genes in the patient and HCs.
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case_images: PMC11791129_01_gr2.jpg
case_images: fig2
case_images: PCR with primer flanking the deleted region generated an approximately 500-bp product only in the patient and his carrier parents but not in the patient's healthy brother or a healthy control sample (Fig 2, A and see Fig E1, B). Sanger sequencing of the amplification product identified a large (~9-kb) deletion of genomic DNA (GRCh38: chr20: 36948791_36957774del) comprising exon 1 of SAMHD1 (Fig 2, B). Quantitative RT-PCR analysis showed a significant reduction in SAMHD1 expression in the patient and an approximately 50% reduction in the parents (Fig 2, C [left panel]). Expression of the interferon-regulated gene ISG15 showed increased expression in the patient compared with in his family members and healthy controls (Fig 2, C [right panel]). A custom-designed NanoString-RNA expression array of 31 interferon-regulated and other inflammatory genes showed upregulation of interferon-stimulated genes in the peripheral blood of the patient versus in the healthy controls (Fig 2, D). We therefore performed PCR with flanking primers and expression analysis to exclude a carrier status in the patient's brother (Fig 2, A and C).