Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2025 Apr 1.
Published in final edited form as: Am J Med Genet A. 2023 Dec 1;194(4):e63486. doi: 10.1002/ajmg.a.63486

SAMHD1 compound heterozygous rare variants associated with moyamoya and mitral valve disease in the absence of other features of Aicardi-Goutières syndrome

Aamuktha R Karla 1,*, Amélie Pinard 1,*, Maura L Boerio 1, Dimitri Hemelsoet 2, Simon J Tavernier 3, Michel De Pauw 4, Elke Vereecke 5, Stuart Fraser 6, Michael J Bamshad 7, Dongchuan Guo 1, Bert Callewaert 8, Dianna M Milewicz 1
PMCID: PMC11700514  NIHMSID: NIHMS1946934  PMID: 38041217

Abstract

Aicardi-Goutières syndrome (AGS) is an autosomal recessive inflammatory syndrome that manifests as an early-onset encephalopathy with both neurologic and extraneurologic clinical findings. AGS has been associated with pathogenic variants in 9 genes: TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR, IFIH1, LSM11, and RNU7–1. Diagnosis is established by clinical findings (encephalopathy and acquired microcephaly, intellectual and physical impairments, dystonia, hepatosplenomegaly, sterile pyrexia, and/or chilblains), characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes), or the identification of pathogenic/likely pathogenic variants in the known genes. One of the genes associated with AGS, SAMHD1, has also been associated with a spectrum of cerebrovascular diseases, including moyamoya disease (MMD). In this report, we describe a 31-year-old male referred to genetics for MMD since childhood who lacked the hallmark features of AGS patients but was found to have compound heterozygous SAMHD1 variants. He later developed mitral valve insufficiency due to recurrent chordal rupture and ultimately underwent a heart transplant at 37 years of age. Thus, these data suggest that SAMHD1 pathogenic variants can cause MMD without typical AGS symptoms and support that SAMHD1 should be assessed in MMD patients even in the absence of AGS features.

Keywords: moyamoya disease, SAMHD1, Aicardi-Goutières syndrome, stroke

INTRODUCTION

Aicardi-Goutières syndrome (AGS) is an inherited type I interferonopathy first described in 1984 (Aicardi & Goutieres, 1984) in children with increased serum and cerebrospinal fluid (CSF) interferon-α activity and associated IFN-stimulated genes (ISGs). As of 2020, nine genes have been implicated in the causation of AGS: TREX1 (AGS1, MIM: 225750), RNASEH2B (AGS2, MIM: 610181), RNASEH2C (AGS3, MIM: 610329), RNASEH2A (AGS4, MIM: 610333), SAMHD1 (AGS5, MIM: 612952), ADAR (AGS6, MIM: 615010), IFIH1 (AGS7, MIM: 615846) LSM11 (AGS8, MIM: 619486) and RNU7–1 (AGS9, MIM: 619487) (Uggenti et al., 2020). The syndrome is usually associated with severe intellectual and physical impairments, and patients present primarily prenatally or within the first year of life, with few cases presenting with later onset (Livingston et al., 2016). Neurologic findings associated with AGS may include progressive encephalopathy, developmental delay, neurologic regression, microcephaly, seizures, dystonia, spasticity, spastic paraparesis, eye movement abnormalities, striatal necrosis, basal ganglia calcification, white matter abnormalities, and cerebral atrophy. Non-neurologic symptoms have also been reported, including chilblains, sterile pyrexias, glaucoma, hepatosplenomegaly, hypothyroidism, thrombocytopenia, and cardiomyopathy (Crow, 1993; Livingston et al., 2016).

AGS patients with pathogenic SAMHD1 variants may also have cerebrovascular disease, specifically steno-occlusive lesions in the distal carotid artery and its branches with collateral artery formation consistent with moyamoya disease (MMD) (Barrit, 2018; Brar et al., 2021; Garau et al., 2019; Ramesh et al., 2010; Thiele et al., 2010; Xin et al., 2011). The case described here has novel biallelic heterozygous SAMHD1 variants, initially presented with MMD in the absence of classic AGS symptoms, and subsequently developed cardiac valvular disease.

CLINICAL REPORT

The proband is a European male who presented at 11 years of age with recurrent frontal headaches accompanied by nausea and vomiting compatible with migraine without aura. He was diagnosed with MMD based on neuro-imaging (images unavailable) following complaints of pain in the legs and a suspected TIA with facial palsy and speech difficulties. He had no chilblains, intellectual impairment, motor abnormalities, microcephaly, or signs of encephalopathy in the neonatal period. There was suspected growth delay during the pregnancy, and length and weight at birth were 46 cm and 2.5 kg, respectively. Neuromotor development during the first year of life was normal, and he attended primary school and trade school until the age of 18 without major problems. At 25 years of age, the patient had a rupture of the chorda tendinea of his mitral valve anterior leaflet with severe mitral regurgitation, which required mitral valve repair. He subsequently developed a symptomatic mitral valve regurgitation and stenosis requiring mitral valve replacement and four subsequent mitral valve interventions due to severe paravalvular leaks at 26, 27, and 37 years of age. At each time, underlying endocarditis was excluded. Ultimately, he underwent a heart transplant at 37 years of age. On exam, he has short stature (166 cm at 37 years of age, P3=168 cm), and neurological examination is normal except for exophoria of the right eye. He still suffers from low frequent migraine attacks. Pertinent family history includes malignant hypertension in his brother, cardiovascular risk factors in his father, stroke in his maternal grandfather, liver failure in his paternal grandfather, and cardiac valve replacement in his paternal grandmother.

A brain MRI at 36 years of age showed occlusion of the central part of the medial and anterior cerebral arteries bilaterally with filling of the cortical branches via collaterals (Figure 1A, 1B, 1C). An extensive network of collaterals is seen in the thalamus bilaterally and around the brainstem. The basilar and vertebral arteries are patent (Figure 1C). Additional MRI findings include focal tissue loss in the superior frontal gyrus consistent with a previous infarct, punctiform white matter lesions in multiple regions, and bilateral cerebral microbleeds.

Figure 1.

Figure 1.

Open in a new tab

(A) Axial T2-weighted MRI showing collateral formation near the brainstem (arrow). (B) Axial magnetic resonance time-of-flight (MR TOF) angiography demonstrating occlusion of bilateral medial and anterior cerebral arteries (arrows). (C) MR TOF angiography demonstrating occlusion of bilateral medial and anterior cerebral arteries (top, sagittal) and patent vertebral and basilar arteries (bottom, coronal). (D) Protein map of the SAMHD1 variants identified in our patient and reported in AGS patients with MMD and/or intracerebral large artery disease. (E) Sanger sequencing of the variants identified in our patient. (F) Increased interferon responsive gene expression is demonstrated in patient samples collected three weeks apart, consistent with biallelic SAMHD1 variants.

The patient and his parents gave consent prior to their inclusion in this study that was approved by the Institutional Review Board of the University of Texas Health Science Center at Houston. Exome sequencing identified compound heterozygous SAMHD1 variants (NM_015474.4) in the proband, c.676C>T, p.(Arg226Cys) (rs778647626) inherited from the mother, and c.1608+2T>C (intron 14) inherited from the father (Figure 1D and 1E). The p.(Arg226Cys) variant was found in two heterozygous carriers in gnomAD control v2.1.1 database (Karczewski et al., 2020) (2 males, 1 African/African American and 1 European (non-Finnish), and the splicing variant c.1608T>C was absent from population databases. Both variants were predicted to be damaging with CADD scores (GRCh37-v1.6) (Rentzsch et al., 2021) of 23.8 for the missense variant, p.(Arg226Cys), and 34 for the splice site variant, c.1608+2T>C (intron 14), and a REVEL score of 0.422 for the missense variant p.(Arg226Cys). SpliceAI analysis confirmed that the splice site variant was damaging with the probability to be a donor loss of function predicted at 0.98 (Jaganathan et al., 2019). Loss of the donor site is predicted to lead to incorrect splicing of exon 14, which will introduce a frameshift and nonsense-mediated RNA decay of the transcript. Thus, current criteria would classify the missense variant p.(Arg226Cys) as a variant of unknown significance and the splice variant as likely pathogenic. Analysis of the exome sequencing data did not identify any pathogenic, likely pathogenic, or variants of unknown significance in other known MMD disease-causing genes.

Our patient was also tested for interferon-stimulated gene expression to generate an ISG score, which has shown to be elevated in patients with variants in SAMHD1 (Crow et al., 2015). Blood was collected at two different time points (three week interval) into PAXgene tubes (PreAnalytix) and, after being kept at room temperature for 2 to 4 hours, was frozen at −80 °C until extraction. Total RNA was extracted using the RNEasy Kit (QIAGEN) following the manufacturer’s instructions. Concentration and purity of RNA was assessed using the NanoDrop 2000 technology. One microgram of RNA was transcribed to cDNA using Sensifast cDNA synthesis kit (Bioline) according to manufacturer’s instructions. Approximately 15 ng cDNA (estimated from input RNA) was used as input for quantitative Real-Time PCR (Light-cycler 480, Roche) and the Sensifast SYBR no ROX kit (Biotin). Differences in cDNA input were corrected using normalization to ACTB cDNA levels. Relative quantitation of the ISG genes SIGLEC1, IFI44L, IFI27, ISG15, RSAD2 and IFIT1 was determined using the ΔΔCt method. The median value of these 6 ISG genes was calculated. The mean ISG score of 6 HCs + 2SD of the mean was calculated and scores above this value were considered positive. The patient was found to have an elevated ISG score (two samples collected three weeks apart, 8.27 and 7.00, ref. healthy controls 3.23), suggesting upregulation of interferon signaling consistent with type I interferonopathy associated with underlying bi-allelic SAMHD1 variants (Figure 1F). The patient had no signs of infection or inflammation at the time of sample collection, and CRP was normal (4.3 and 3.9, ref. <5.0 mg/dL).

DISCUSSION

This report describes a male who was diagnosed at 11 years of age with MMD who went on to have severe mitral valve disease eventually requiring heart transplantation and was identified to have compound heterozygous SAMHD1 rare variants in the absence of classic features of AGS. This patient’s elevated ISG score suggests that his phenotype is likely the result of biallelic variants in SAMHD1. To better characterize this patient in the context of the published literature on SAMHD1 phenotypes, reports of 23 patients with SAMHD1 variants and cerebrovascular pathology were summarized (Barrit, 2018; Brar et al., 2021; Garau et al., 2019; Ramesh et al., 2010; Thiele et al., 2010; Xin et al., 2011). Among these patients, almost half presented with stroke or stenosis of cerebral vessels, eight with MMD, and five with cerebral aneurysms (remarkably, 10 of these patients had two or more types of cerebrovascular pathology). Further, these patients exhibited typical features of AGS, the most common of which were intellectual and/or physical impairment, white matter abnormalities, intracranial calcifications, and chilblains (Table 1). Our patient exhibits only MMD and mitral valve abnormalities and lacks other classic features of AGS.

Table 1.

Cerebrovascular and other clinical findings in previously reported patients with variants in SAMHD1.

Patient Sex Ethnicity Variant(s) Type Moyamoya Aneurysms History of stroke Stenosis of cerebral vessels Other clinical findings
P1 1 F British c.602T>A (p.Ile201Asn) Homozygous + + + Basal ganglia calcification, intellectual and physical disability, chilblains
P2 1 M African c.1503+1G>T, Intron 13 Homozygous + + Intracranial calcification, intellectual and physical disability, hypertonia, glaucoma, chilblains, seizures, cerebral palsy
P3 1 F Canadian c.427C>T (p.Arg143Cys), c.602T>A (p.Ile201Asn) Compound heterozygous + Basal ganglia and periventricular calcification, white matter abnormalities, intellectual disability, microcephaly, chilblains
P4 1 M Italian p.Ex12_Ex16del [unconfirmed] Homozygous + Basal ganglia and periventricular calcification, white matter abnormalities, intellectual and physical disability, spastic tetraparesis, hypotonia, microcephaly, chilblains, seizures
P5 1 M Ashkenazi Jewish c.649insG (p.Phe217Cysfs*2), Deletion of Exon 1 Compound heterozygous + + White matter abnormalities, intellectual and physical disability, tetraplegic, microcephaly, chilblains
P1 2 M Turkish c.490C>T (p.Arg164X) Homozygous + Basal ganglia calcification, intellectual and physical disability, dystonia, psychomotor delay, spasticity, glaucoma, cerebral atrophy, cataracts
P2 2 M Turkish c.490C>T (p.Arg164X) Homozygous + Basal ganglia calcification, microcephaly, dystonia, psychomotor delay, spasticity, glaucoma, chilblains, cerebral atrophy, seizures, cataracts
P3 2 F Turkish c.490C>T (p.Arg164X) Homozygous + Basal ganglia calcification, psychomotor delay, glaucoma, hypothyroidism, chilblains
P4 2 F Turkish c.490C>T (p.Arg164X) Homozygous + + Intracranial calcification, white matter abnormalities, intellectual and physical disability, microcephaly, dystonia, psychomotor delay, spasticity, glaucoma, hypothyroidism, chilblains, cerebral atrophy
P1 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + + Failure to thrive, chilblains
P13 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + + Failure to thrive, white matter abnormalities, developmental delay, glaucoma
P15 3 F Old Order Amish c.1411–2A>G (Intron 12) Homozygous + + Failure to thrive, white matter abnormalities, developmental delay, glaucoma
P16 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + + Failure to thrive, white matter abnormalities, developmental delay
P19 3 F Old Order Amish c.1411–2A>G (Intron 12) Homozygous + White matter abnormalities, spasticity, cerebral palsy
P27 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + Arthritis
P28 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + Arthritis
P29 3 F Old Order Amish c.1411–2A>G (Intron 12) Homozygous + White matter abnormalities, developmental delay, spasticity, glaucoma, cerebral palsy
P33 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + + White matter abnormalities, spasticity
P34 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + White matter abnormalities
P38 3 M Old Order Amish c.1411–2A>G (Intron 12) Homozygous + [Newborn with no presenting symptoms, variant found through requested DNA testing]
P1 4 M Turkish Variant unspecified Homozygous + Basal ganglia calcification, white matter abnormalities, physical disability, dystonia, spasticity, microcephaly, chilblains, epilepsy
P41 5 M Italian p.Ex12_Ex16del Homozygous + Intracranial calcification, white matter abnormalities, cerebral vasculitis, intracerebral hematoma, intellectual and physical disability, spastic tetraparesis, dystonia, epilepsy
P1 6 F Old Order Amish c.1411–2A>G (Intron 12) Homozygous + + + Basal ganglia calcification, white matter abnormalities
Our patient M Belgian c.676C>T (p.Arg226Cys),
c.1608+2T>C (Intron 14)		 Compound heterozygous + Mitral valve rupture, mitral regurgitation
Open in a new tab

The CADD and REVEL scores (23.8 and 0.422, respectively) for our patient’s missense variant, p.Arg226Cys, are lower than those of previously reported missense variants, suggesting that our patient’s variant may cause less damage to the protein and thus presents with none of the classic AGS findings. Specifically, Ramesh et al. reported the variant p.Ile201Asn with a CADD score of 29.1 and REVEL score of 0.901, and the variant p.Arg143Cys with a CADD score of 29.2 and REVEL score of 0.947. Patients with both variants exhibited classic AGS findings, including basal ganglia calcification, intellectual impairment, and chilblains.

Prior reports have not shown an association between cardiac valvular pathology and SAMHD1 variants. One recent study reported three patients with compound heterozygous variants in a different AGS-associated gene, ADAR. These patients presented with calcifications of the valve leaflets, mitral stenosis, mitral regurgitation, aortic stenosis, and tricuspid regurgitation (Crow et al., 2020). Additional longitudinal studies will determine if mitral valvular disease is a common finding in AGS patients due to SAMHD1 variants. Moreover, the family history of our patient was notable for valvular disease and may suggest additional genetic risk factors.

In terms of management of these patients, it has been suggested that patients with biallelic pathogenic variants in SAMHD1 should be screened for intracranial vasculopathy (Crow, 1993). Likewise, patients presenting with MMD with or without AGS should be considered for genetic testing of the known genes for MMD, and these analyses should include SAMHD1. Depending on the patient’s clinical presentation and history, early intervention may allow for improvement of cerebral vasculopathy or prevention of progression. Prior research has shown that SAMHD1 has a role in regulating the innate immune response, specifically by inhibiting activation of the NF-κB and interferon (IFN-I) pathways in cells (Chen et al., 2018). Inhibition of IL-6, which is activated by NF-κB, using tocilizumab improved cerebrovascular disease in a 19-year-old male with homozygous SAMHD1 variants and diffuse moyamoya angiopathy on MRA, and such treatments could be considered to prevent or reverse the cerebrovascular disease in other MMD patients with SAMHD1 variants (Xin et al., 2011; Henrickson & Wang, 2017).

Acknowledgements:

We are grateful to the patient and his family members for participating in this study. This study was funded by NIH R01HL109942, an American Heart Association Merit Award (D.M.M.), the Henrietta B. and Frederick H. Bugher Foundation (D.M.M.), the Texas Heart Institute Fibromuscular Dysplasia Project (D.M.M.), and AHA Postdoctoral Fellowship (18POST34020031; A.P.). Exome sequencing was funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute grant HG006493 to Deborah Nickerson, M.J.B., and Suzanne Leal. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Authors of this publication (B.C., D.H.) are members of the European Reference Network (ERN) for Developmental Anomalies and Intellectual Disability (ERN-ITHACA) and Rare Neurological Diseases (ERN-RND) and participate in the Solve-RD Project (https://solve-rd.eu/).

Footnotes

Conflict of Interest: The authors declare no conflicts of interest.

Data availability statement:

Study data for the primary analyses presented in this report are available on request from the corresponding author.

References

  1. Aicardi J, & Goutieres F. (1984). A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Annals of Neurology, 15(1), 49–54. doi: 10.1002/ana.410150109. [DOI] [PubMed] [Google Scholar]
  2. Barrit S. (2018). An Aicardi-Goutieres syndrome associated with a quasi-Moyamoya by a biallelic mutation in SAMHD1. [Syndrome d’Aicardi-Goutieres associe a un quasi-Moyamoya par une mutation biallelique de SAMHD1] Revue Medicale De Bruxelles, 39(3), 155–160. doi: 10.30637/2018.16-030. [DOI] [PubMed] [Google Scholar]
  3. Brar JS, Verma R, Al-Omari M, Siu VM, Andrade AV, Jurkiewicz MT, & Lalgudi Ganesan S. (2021). Moyamoya Syndrome in an Infant with Aicardi-Goutieres and Williams Syndromes: A Case Report. Neuropediatrics, 53(3), 204–207. doi: 10.1055/s-0041-1739131. [DOI] [PubMed] [Google Scholar]
  4. Chen S, Bonifati S, Qin Z, St. Gelais C, Kodigepalli KM, Barrett BS, Kim SH, Antonucci JM, Ladner KJ, Buzovetsky O, Knecht KM, Xiong Y, Yount JS, Guttridge DC, Santiago ML, & Wu L. (2018). SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways. Proceedings of the National Academy of Sciences of the United States of America, 115(16), E3798–E3807. doi: 10.1073/pnas.1801213115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Crow YJ (2016). Aicardi-Goutieres Syndrome. In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM & Amemiya A. (Eds.), GeneReviews. University of Washington, Seattle. [PubMed] [Google Scholar]
  6. Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, Oojageer A, Anderson B, Pizzino A, Helman G, Abdel-Hamid MS, Abdel-Salam GM, Ackroyd S, Aeby A, Agosta G, Albin C, Allon-Shalev S, Arellano M, Ariaudo G, . . . Rice GI. (2015). Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American Journal of Medical Genetics Part A, 167A(2), 296–312. doi: 10.1002/ajmg.a.36887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Crow Y, Keshavan N, Barbet JP, Bercu G, Bondet V, Boussard C, Dedieu N, Duffy D, Hully M, Giardini A, Gitiaux C, Rice GI, Seabra L, Bader-Meunier B, & Rahman S. (2020). Cardiac valve involvement in ADAR-related type I interferonopathy. Journal of Medical Genetics, 57(7), 475–478. doi: 10.1136/jmedgenet-2019-106457. [DOI] [PubMed] [Google Scholar]
  8. Garau J, Cavallera V, Valente M, Tonduti D, Sproviero D, Zucca S, Battaglia D, Battini R, Bertini E, Cappanera S, Chiapparini L, Crasa C, Crichiutti G, Dalla Giustina E, D’Arrigo S, De Giorgis V, De Simone M, Galli J, La Piana R, . . . Cereda C. (2019). Molecular Genetics and Interferon Signature in the Italian Aicardi Goutieres Syndrome Cohort: Report of 12 New Cases and Literature Review. Journal of Clinical Medicine, 8(5), doi: 10.3390/jcm8050750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Henrickson M, & Wang H. (2017). Tocilizumab reverses cerebral vasculopathy in a patient with homozygous SAMHD1 mutation. Clinical Rheumatology, 36(6), 1445–1451. doi: 10.1007/s10067-017-3600-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, Kosmicki JA, Arbelaez J, Cui W, Schwartz GB, Chow ED, Kanterakis E, Gao H, Kia A, Batzoglou S, Sanders SJ, & Farh KK (2019). Predicting Splicing from Primary Sequence with Deep Learning. Cell, 176(3), 535–548. doi: 10.1016/j.cell.2018.12.015. [DOI] [PubMed] [Google Scholar]
  11. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, . . . MacArthur DG. (2020). The mutational constraint spectrum quantified from variation in 141,456 humans. Nature, 581(7809), 434–443. doi: 10.1038/s41586-020-2308-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Livingston JH, & Crow YJ (2016). Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutieres Syndrome and beyond. Georg Thieme Verlag KG. doi: 10.1055/s-0036-1592307. [DOI] [PubMed] [Google Scholar]
  13. Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, & Crow YJ (2010). Intracerebral large artery disease in Aicardi-Goutieres syndrome implicates SAMHD1 in vascular homeostasis. Developmental Medicine and Child Neurology, 52(8), 725–732. doi: 10.1111/j.1469-8749.2010.03727.x. [DOI] [PubMed] [Google Scholar]
  14. Rentzsch P, Schubach M, Shendure J, & Kircher M. (2021). CADD-Splice-improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Medicine, 13(1), 31–9. doi: 10.1186/s13073-021-00835-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Thiele H, du Moulin M, Barczyk K, George C, Schwindt W, Nürnberg G, Frosch M, Kurlemann G, Roth J, Nürnberg P, & Rutsch F. (2010). Cerebral Arterial Stenoses and Stroke: Novel Features of Aicardi-Goutières Syndrome Caused by the Arg164X Mutation in SAMHD1 Are Associated with Altered Cytokine Expression. Human Mutation, 31(11), E1836–E1850. doi: 10.1002/humu.21357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Uggenti C, Lepelley A, Depp M, Badrock AP, Rodero MP, El-Daher MT, Rice GI, Dhir S, Wheeler AP, Dhir A, Albawardi W, Fremond ML, Seabra L, Doig J, Blair N, Martin-Niclos MJ, Della Mina E, Rubio-Roldan A, Garcia-Perez JL, . . . Crow YJ. (2020). cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. Nature Genetics, 52(12), 1364–1372. doi: 10.1038/s41588-020-00737-3. [DOI] [PubMed] [Google Scholar]
  17. Xin B, Jones S, Puffenberger EG, Hinze C, Bright A, Tan H, Zhou A, Wu G, Vargus-Adams J, Agamanolis D, & Wang H. (2011). Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke. Proceedings of the National Academy of Sciences of the United States of America, 108(13), 5372–5377. doi: 10.1073/pnas.1014265108. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Study data for the primary analyses presented in this report are available on request from the corresponding author.

RESOURCES