Screening Newborns for Low T Cell Receptor Excision Circles (TRECs) Fails to Detect Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome

Staudacher, Olga; Klein, Jeanette; Thee, Stephanie; Ullrich, J Grasa; Wahn, V.; Unterwalder, Nadine; Kölsch, Uwe; Lankes, Erwin; Stittrich, Anna Barbara; Dedieu, Cinzia; Dinges, Sarah S.; Völler, Mirjam; Schuetz, Catharina; Schulte, Johannes H.; Boztuğ, Kaan; Meisel, Christian; Kuehl, Jörn-Sven; Krüger, Renate; Blankenstein, Oliver; Bernuth, Horst von

doi:10.1016/j.jaip.2023.06.006

Cited by 3 publications

(2 citation statements)

References 104 publications

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“…It is a clinically heterogeneous disorder consisting of variable combined immunodeficiency and variable neurological impairments ( 2 , 3 ). The disease was primarily described as a humoral syndrome, but the broad altered clinical spectrum demonstrates a dysregulation of T-cell function ( 2 , 4 ).…”

Section: Introductionmentioning

confidence: 99%

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A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Lullo,

Cecere,

Batti

et al. 2024

Front. Immunol.

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Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.

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Section: Introductionmentioning

confidence: 99%

“…Subtype 2 accounts for about 30% of ICF cases. In these patients, immunodeficiency signs often manifest progressively during their lifetime, characterized as a combined immunodeficiency ( 4 , 14 , 15 ). Autoimmunity predisposition, inflammatory bowel diseases and malignancies have also been reported in ICF2 patients ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Lullo,

Cecere,

Batti

et al. 2024

Front. Immunol.

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Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome

Bilgic Eltan,

Nain,

Catak

et al. 2023

J Clin Immunol

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Allogeneic Hematopoietic Stem Cell Transplantation in Immunodeficiency—Centromeric Instability—Facial Dysmorphism (ICF) Syndrome: an EBMT/ESID Inborn Errors Working Party Study

Berghuis,

Mehyar,

Abu-Arja

et al. 2024

J Clin Immunol

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Immunodeficiency–Centromeric instability–Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003–2021, at median age 4.3 years (range 0.5–19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1–185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1–14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome.

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Screening Newborns for Low T Cell Receptor Excision Circles (TRECs) Fails to Detect Immunodeficiency, Centromeric Instability, and Facial Anomalies Syndrome

Cited by 3 publications

References 104 publications

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Evaluation of Clinical and Immunological Alterations Associated with ICF Syndrome

Allogeneic Hematopoietic Stem Cell Transplantation in Immunodeficiency—Centromeric Instability—Facial Dysmorphism (ICF) Syndrome: an EBMT/ESID Inborn Errors Working Party Study

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