Publications
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Andersen, Jintana Bunpan; Strand, Janne Maren; Stray-Pedersen, Asbjørg; Abrahamsen, Tore Gunnar; Stray-Pedersen, Arne & Flægstad, Trond
[Show all 9 contributors for this article]
(2026).
Unmasking immunodeficiency in sudden infant deaths: no evidence of hidden immune disorders.
Frontiers in Immunology.
17.
doi:
10.3389/fimmu.2026.1860011.
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Introduction Sudden infant death syndrome (SIDS) remains a leading cause of post-neonatal mortality, yet its underlying mechanisms are largely unknown. Evidence suggests that immune dysfunction may play a role in a subset of cases. However, the role of inborn errors of immunity (IEI), particularly severe combined immunodeficiency (SCID), has not been systematically explored. We aimed to study their potential role in SIDS and infant deaths from infectious disease. Methods We obtained mortality data for 2012–2017 from The Norwegian Cause of Death Registry and identified eligible infants by reviewing ICD-10 codes for infection-related deaths or SIDS. The medical history and autopsy reports were reviewed and infants with predisposition to infection were excluded. Genetic testing was performed on biobanked newborn dried blood spot samples following the protocol for identifying SCID/IEI in live-born infants. Results The study population consisted of 79 infants, of which 66% ( n = 52) died of SIDS and 34% ( n = 27) due to infection. The majority of the infants in both groups had at least one genetic IEI-related variant, but no findings were clearly pathogenic. Variants of uncertain significance in autosomal dominant disease genes were identified in 18% ( n = 14). Heterozygous pathogenic variants in autosomal recessive genes were identified in 23% ( n = 18). Risk factor variants were identified in 42% ( n = 33), including two mannose-binding lectin 2 polymorphisms with alleles more frequently observed in the infection group compared to the general population. Discussion No missed cases of SCID/IEI were identified among infants who died from infections or SIDS. Yet a significant proportion of the cohort may carry genetic predispositions due to the presence of immune-related genetic variants. Even in the absence of overt immunodeficiency, these findings may reflect a latent vulnerability interacting with physiological and environmental factors.
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Martinsen, Karen Marie Bronken; Øverland, Torstein; Stray-Pedersen, Asbjørg; Abrahamsen, Tore Gunnar; Fevang, Børre & Landsverk, Hans Christian Erichsen
(2025).
A Norwegian cohort with STAT1-related disease – further expanding the clinical phenotype.
Frontiers in Immunology.
16.
doi:
10.3389/fimmu.2025.1620291.
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Purpose: Inborn errors of immunity (IEIs) caused by mutations in STAT1 are associated with a broad range of clinical manifestations, ranging from relatively mild to life-threatening. Our aim was to give a clinical and molecular description of a Norwegian cohort with STAT1-related disease.
Methods: This is a descriptive epidemiological study.
Results: We present 23 patients with heterozygous STAT1 mutations, from 12 unrelated Norwegian families. Eighteen individuals had STAT1 gain-of-function (GOF) variants. Chronic mucocutaneous candidiasis (CMC) was the most common manifestation, observed in 94% of patients. Herpesviruses caused morbidity in one-third of patients, with severe complications such as varicella meningitis, varicella retinitis and ulcerative CMV esophagitis seen in 17%. Autoimmune hypertriglyceridemia with GPIHBP1 autoantibodies was diagnosed in one patient, adding a new entity to STAT1 GOF. Fifty percent of patients suffered chronic ophthalmologic manifestations. Severe gastrointestinal manifestations were observed in 22% of patients. Five of the 23 patients had STAT1 loss-of-function (LOF) variants. Mendelian susceptibility to mycobacterial disease (MSMD) was detected in three patients. Malignancy and autoimmunity were observed in two patients, both were heterozygous for the p.Ala246Thr variant, which is likely associated with a more complex phenotype. Significant viral infections were also observed. Presently, our cohort represents the largest nationwide study on STAT1-related disease.
Conclusion: We report novel clinical manifestations in STAT1 GOF, and suggest that heterozygous STAT1 LOF might be a more complex condition than originally presumed.
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Mamia, Katariina Aino Inkeri; Kolbeinsdottir, Solrun; Labun, Kornel; Li, Zhuokun; Komisarczuk, Anna Zofia & Keskitalo, Salla
[Show all 32 contributors for this article]
(2025).
Precision T cell correction platform for Inborn Errors of Immunity.
Molecular Therapy.
ISSN 1525-0016.
33(11),
p. 5624–5643.
doi:
10.1016/j.ymthe.2025.08.018.
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CRISPR/Cas9 gene editing is a promising tool to correct pathogenic variants for autologous cell therapies targeting Inborn errors of immunity (IEI). Current strategies, such as gene knockout or cDNA knock-in, address many single-gene defects but can disrupt gene expression, highlighting the need for precise correction platforms. While transplanting corrected autologous hematopoietic stem cells is a curative approach, it is unsuitable for patients with advanced disease, inflammation or acute infections. As correcting T cells is an alternative therapeutic strategy for lymphoid IEIs, we present an efficient T cell single nucleotide variant (SNV) correction platform based on homology-directed repair (HDR). By using STAT1 gain-of-function (STAT1-GOF), Cartilage Hair Hypoplasia (CHH), Deficiency of ADA2 (DADA2), and Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as IEI models, we demonstrate that our platform achieves up to 80% correction, with resultant functional correction of the disease phenotype in the selected models. Furthermore, we performed safety profiling using GUIDE-seq, single-cell RNA sequencing, long-read genome sequencing, and proteomics analysis and detected no genomic, transcriptomic, or proteomic aberrations. This study establishes HDR-based SNV editing as a portable method for developing clinical autologous T cell therapies and represents a promising step toward a broad-spectrum gene correction platform for treating diverse monogenic immune disorders.
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Berg, Annika Klungland; Diseth, Trond H; Abrahamsen, Tore G; Halvorsen, Kathleen; Reinfjell, Trude & Erichsen, Hans Christian
(2021).
Primary antibody deficiency: The impact on the quality of life and mental health of affected children and their parents.
Acta Paediatrica.
ISSN 0803-5253.
110,
p. 1645–1652.
doi:
10.1111/apa.15752.
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Aim To evaluate health-related quality of life, mental health and treatment-related stress responses in children with primary antibody deficiency and both their parents. Methods Children and their parents completed the standardised questionnaires Pediatric Quality of life Inventory, Strength and Difficulties Questionnaire and Impact of Event Scale. Parents also completed standardised questionnaires regarding their own mental health and quality of life. The results were compared to those of healthy children, kidney transplanted children and children in remission from acute lymphoblastic leukaemia. Results Children with primary antibody deficiency reported a poorer health-related quality of life compared to healthy children and children in remission from acute lymphoblastic leukaemia. They reported poorer mental health compared with healthy children. Mothers of children with primary antibody deficiency reported poorer mental health compared to mothers of healthy children but comparable to mothers of chronically ill children. Parents reported a similar quality of life as the general Norwegian population. Treatment with subcutaneous immunoglobulin infusions at home is generally well tolerated, but some report severe treatment-related stress. Conclusion Primary antibody deficiency has a significant impact on quality of life and mental health of affected children. Patients and parents with severe treatment-related stress should be identified and helped.
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Strand, Janne Maren; Gul, Kiran Aftab; Erichsen, Hans Christian; Lundman, Emma; Berge, Mona C. & Trømborg, Anette Kjoshagen
[Show all 28 contributors for this article]
(2020).
Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency.
Frontiers in Immunology.
11.
doi:
10.3389/fimmu.2020.01417.
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Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.
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Lam, Michael T.; Coppola, Simona; Krumbach, Oliver H.F.; Prencipe, Giuseppe; Insalaco, Antonella & Cifaldi, Cristina
[Show all 60 contributors for this article]
(2019).
A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.
Journal of Experimental Medicine (JEM).
ISSN 0022-1007.
216(12),
p. 2778–2799.
doi:
10.1084/jem.20190147.
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Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990CT, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.
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Stray-Pedersen, Asbjørg; Sorte, Hanne Sørmo; Samarakoon, Pubudu Saneth; Gambin, Tomasz; Chinn, Ivan K. & Akdemir, Zeynep H.C.
[Show all 51 contributors for this article]
(2016).
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.
Journal of Allergy and Clinical Immunology.
ISSN 0091-6749.
139(1),
p. 232–245.
doi:
10.1016/j.jaci.2016.05.042.
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Background Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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Haugen, Frida Loe; Mamia, Katariina Aino Inkeri; Rio, Oline Eriksen; Sollano, Anniken Solveig Matheson; Li, Zhuokun & Labun, Kornel
[Show all 20 contributors for this article]
(2025).
CRISPR-Cas9 pipeline for custom editing in autologous T cells.
doi:
https:/event.fourwaves.com/crisprmed25/abstracts/b5911e8e-de8e-4ee4-b8e2-9f08cc2f31d8.
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CRISPR/Cas9 gene editing technology is a promising tool for correcting pathogenic variants in Inborn Errors of Immunity (IEIs). Current IEI correction strategies rely on cDNA knock-in or gene knockout, which can disrupt gene expression and need extensive optimization. To address this, we developed a safe, efficient CRISPR/Cas9-based T cell editing pipeline using HDR for SNV correction.
We observe a rapid and selective expansion of CD3+ T cells from patient peripheral blood following an 8-day cytokine stimulation. To enhance HDR outcomes, we explored multiple strategies and developed an optimized T cell pipeline capable of achieving up to 80% HDR. We found no pre-malignant off-target effects or karyotypic, transcriptomic, or proteomic abnormalities in patient T cells analysed with GUIDE-seq, scRNA-seq, long-read WGS, and proteomics. We observed functional correction of the disease phenotype in patient T cells demonstrated on transcriptomic level by single cell RNA sequencing, on proteomic level by Mass Spectrometry and in cell culture-based assays.
So far, we have implemented the pipeline and corrected 12 unique SNV mutations causing 8 diverse IEIs. This platform is designed to streamline CRISPR tool discovery/optimization and can be further developed into a GMP-compatible, scaled-up process for salvage therapy in T cell-related IEIs.
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Landsverk, Hans Christian Erichsen
(2023).
Kurativ behandling av monogenetiske sykdommer med genterapi. En ny tidsalder.
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Landsverk, Hans Christian Erichsen; Almaas, Runar & Saugstad, Ola Didrik
(2022).
50 Years Ago in THE JOURNAL OF PEDIATRICS: Hemiallogeneic Stem Cell Transplantation—from Last Resort to a Viable Treatment Option.
Journal of Pediatrics.
ISSN 0022-3476.
243,
p. 213–213.
doi:
10.1016/j.jpeds.2021.12.064.
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Stray-Pedersen, Asbjørg; Backe, Paul Hoff; Sorte, Hanne Sørmo; Mørkrid, Lars; Chokshi, N.Y. & Erichsen, Hans Christian
[Show all 39 contributors for this article]
(2014).
A congenital disorder of glycosylation, with lymphopenia,
neutropenia, and skeletal dysplasia, caused by mutations in the gene encoding phosphoglucomutase 3 (PGM3).
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Stray-Pedersen, Asbjørg; Sorte, Hanne Sørmo; Rødningen, Olaug Kristin; Lyle, Robert; Gonzaga-Jauregui, C G & Hanson, C I
[Show all 16 contributors for this article]
(2012).
THE UTILITY OF EXOME SEQUENCING IN PRIMARY IMMUNODEFICIENCY DISEASES AND IMMUNODYSREGULATIVE DISORDERS.
Journal of Clinical Immunology.
ISSN 0271-9142.
32(Supp. 1),
p. 184–185.
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Abrahamsen, Tore G & Erichsen, Hans Christian
(2007).
Single Nucleotide Polymorphisms in Genes Encoding Vitamin C Transport Proteins and Inflammatory Cytokines: Risk of Colon Adenoma and Preterm Birth.
Universitetet i Oslo.
ISSN 9788280726834.
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Forsker og lege på barneavdelingen på Sykehuset Buskerud HF, Hans Christian Erichsen, har påvist en sammenheng mellom C vitamin og for tidlig fødsel. Prosjektet som ble utført ved National Institutes of Health i USA, er viktig av flere årsaker. For tidlig fødsel, dvs. mer enn tre uker før termin, er en av hovedårsakene til sykehusinnleggelse av spedbarn. Videre er for tidlig fødte barn mer utsatt for mange sykdommer enn barn født til termin. Sykehusinnleggelse og sykdom hos nyfødte medfører en stor belastning for foreldre og barn og er i tillegg også svært ressurskrevende for samfunnet. Det er tidligere påvist en sammenheng mellom lavt inntak av frukt og grønnsaker og for tidlig fødsel. En har antatt at C vitamin spiller en viktig rolle uten at en har kunnet fastslå dette sikkert. I doktoravhandlingen ”Single Nucleotide Polymorphisms in Genes Encoding Vitamin C Transport Proteins and Inflammatory Cytokines: Risk of Colon Adenoma and Preterm Birth” har Erichsen og hans kollegaer kartlagt og analysert to gener som er viktige for C vitamin transport i kroppen. Ved å analysere DNA hos ca. 250 kvinner som fødte for tidlig, og hos ca. 500 kvinner som fødte til termin, kunne en påvise at kvinner med en vanlig variant (hos 30%) av det ene genet, har tre ganger høyere risiko enn andre for å føde for tidlig. Resultatene fra dette forskningsarbeidet knytter for tidlig fødsel direkte til et av genene for C vitamin transport og støtter tidligere forskning som viser at lavt inntak av C vitamin kan øke risikoen for å føde for tidlig. I doktorgradsarbeidet undersøkte en også betydningen av C vitamin transport genene i forhold til risiko for tykktarmskreft. Resultatene kan tyde på at en genvariant er forbundet med redusert risiko for kreftutvikling.
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Published
Feb. 12, 2019 10:37 AM
- Last modified
Feb. 12, 2019 10:37 AM
