Zeta-chain-associated protein kinase 70 (ZAP-70) deficiency, a rare form of combined immunodeficiency (CID), is caused by homozygous or compound heterozygous variants in the ZAP70 gene. ZAP-70, a tyrosine kinase, plays a key role in T-cell receptor (TCR) signaling, which is critical for T cell activation. ZAP-70 deficiency manifests clinically in a variety of ways, including recurring respiratory infections and cutaneous manifestations. This study describes the clinical, genetic, and immunological characteristics of four Turkish, two Syrian, and one Azerbaijani patient with ZAP-70 deficiency, including two novel variants. Among seven patients diagnosed with ZAP-70 deficiency, two previously unreported ZAP70 variants were identified. Functional analyses performed in four patients—including three with novel variants—demonstrated impaired TCR-induced proliferation, reduced Interleukin 2 (IL-2) production, and markedly diminished CD8⁺ T cell numbers, supporting the pathogenicity of these variants. Clinical phenotypes were heterogeneous, ranging from severe early-onset infections and cytopenias to autoimmune manifestations and atopy. Notably, even siblings carrying the same variant exhibited divergent immunological profiles and disease severity, highlighting the influence of potential genetic or environmental modifiers. Hematopoietic stem cell transplantation (HSCT) was curative in four patients, while one patient died before transplant. This report expands the genetic and phenotypic spectrum of ZAP-70 deficiency by describing two novel variants and emphasizing the value of functional analysis in variant classification and patient management. The online version contains supplementary material available at 10.1007/s10875-026-01989-0.

Severe combined immunodeficiency (SCID) and other profound T- and B-cell lymphopenias are life-threatening conditions that benefit from early diagnosis and treatment. In October 2022, Ukraine launched a nationwide newborn screening (NBS) program for SCID using the T-cell receptor excision circle/kappa-deleting recombination excision circle/spinal muscular atrophy (TREC/KREC/SMA) assay, despite ongoing war-related challenges. The aim of this study was to analyze the results of the SCID NBS program in Ukraine, evaluate its effectiveness, and outline the current challenges and future directions for its development. We analyzed data of screened newborns for SCID and related lymphopenias using the TREC/KREC/SMA assay from October 2022 to April 2025. The results of lymphocyte flow cytometry values, genetic testing, and clinical management of patients with positive TREC/KREC results were evaluated. Among 398,415 screened newborns, 57 were identified with positive results (32 TREC ± KREC and 25 only KREC). The program demonstrated a high diagnostic yield, with an overall referral rate of 0.01%. In total, 18 newborns with inborn errors of immunity were diagnosed due to NBS (7 SCID/leaky SCID and 11 non-SCID). One case of ZAP70 deficiency was missed due to normal levels of T cells. The incidence of SCID/leaky SCID detected by NBS was 1 in 57,000 live births, and 1 in 49,800 live births when all diagnosed cases, including one initially missed case, were taken into account, which is comparable to data from other countries. All patients with SCID/leaky SCID identified by NBS received hematopoietic stem cell transplantation, with a survival rate of 85.7%. Nijmegen breakage syndrome was the most common syndromic cause of non-SCID T-cell lymphopenias (three cases). The use of the KREC assay enabled the first-time identification in Ukraine of B-cell lymphopenias associated with variants in IGLL1 gene. The nationwide NBS program in Ukraine demonstrated high sensitivity and specificity in detecting SCID, with a low referral rate and high survival rates among diagnosed patients.

Zeta-chain-associated protein kinase 70 (ZAP70) deficiency is a rare autosomal recessive T+B+NK+ combined immunodeficiency characterized by heterogeneous clinical and immunologic phenotypes. Because of the limited number of reported cases, data guiding optimal management and hematopoietic stem cell transplantation (HSCT) strategies remain scarce. We retrospectively reviewed all patients with genetically confirmed ZAP70 deficiency treated at King Faisal Specialist Hospital and Research Centre. Data on pre-HSCT clinical and immunologic features, transplant characteristics, post-HSCT complications, immune reconstitution, and long-term outcomes were recorded. Thirteen patients with a median age at symptom onset of 1 month were identified. The most frequent initial presentations were recurrent respiratory infections and cutaneous manifestations. Autoimmune complications and lymphoproliferation were observed in several patients. Eleven of thirteen patients (84.6%) exhibited profound CD8+ T-cell lymphopenias and two had near-normal CD8+ T-cell counts with impaired T-cell function. Eleven patients underwent HSCT, including seven from Human Leukocyte Antigen (HLA)-matched family donors, two from one-antigen mismatched related donors, one from a haploidentical mother (matched for graft-versus-host disease risk but mismatched for rejection), and one from an unrelated cord blood donor. Two patients required a second transplant because of poor immune reconstitution. Of the 11 patients who underwent HSCT, 8 (73%) remain alive with a median follow-up of 7 years (range, 1-15), and most demonstrated resolution of clinical manifestations. HSCT remains the only curative treatment for ZAP70 deficiency. Myeloablative conditioning regimens appear to promote more robust and durable immune reconstitution. In critically ill patients with severe infections or end-organ damage, reduced-intensity or unconditioned HSCT can be considered as a life-saving approach, although subsequent interventions might be necessary.

Zeta-chain-associated protein kinase 70 (ZAP70) is a tyrosine kinase that plays a crucial role in T-cell activation via the T-cell receptor/CD3 complex and contributes to B-cell signaling. ZAP70 variants can cause a range of immunodeficiencies with variable clinical presentations, including infections and malignancies. A 4-year-old boy presented with chronic cough, dyspnea, recurrent chest infections, and failure to thrive. Chest radiography revealed diffuse bilateral opacities, suggesting a diagnosis of diffuse familial bronchiectasis. Immunological workup at 18 years of age showed CD4+ and CD8+ T-cell lymphopenia, and genetic analysis revealed a homozygous pathogenic ZAP70 splice-site mutation (c.402 + 2 T>C). The patient then developed headaches, dizziness, and double vision, and Epstein-Barr virus (EBV) polymerase chain reaction (PCR) testing revealed a viral load of 700 IU/mL. Magnetic resonance imaging (MRI) revealed three brain lesions, and brain biopsy confirmed EBV-positive CD20 + diffuse large B-cell lymphoma (DLBCL). Despite aggressive chemotherapy and palliative radiotherapy, the patient's condition deteriorated, resulting in death. To our knowledge, this is the first known case of primary central nervous system DLBCL in a patient with a novel ZAP70 variant. ZAP70 deficiency is typically associated with combined immunodeficiency and rarely with malignancies such as leukemia or lymphoma. Genetic screening at earlier stages could have potentially identified this underlying immunodeficiency sooner and altered the management course. This case underscores the diagnostic challenges and aggressive course of ZAP70-related disease and highlights the need for increased clinical suspicion, immunologic surveillance, early genetic screening, and development of targeted therapies.

Individuals with inborn errors of immunity face challenges in fertility, pregnancy, and genetic disorder transmission. Prenatal genetic counseling is crucial, especially in tribal societies with consanguineous unions. Ten families with confirmed inborn errors of immunity were studied, revealing diverse pregnancy decisions: An architect with autosomal dominant STAT-1 gain of function underwent prenatal diagnosis despite initial plans for preimplantation genetic diagnosis. In a consanguineous family, two children died from leukocyte adhesion deficiency type 1 because the father refused prenatal diagnosis. First cousins opted against terminating the second pregnancy, resulting in two children affected by Bruton disease. Another consanguineous couple, with two children afflicted by ataxia-telangiectasia, chose oocyte donation for their third child, ensuring a healthy birth. Recurrent pregnancy loss was observed in a mother subsequently diagnosed with ZAP70 deficiency. A mother with Wiskott-Aldrich syndrome child opted for in vitro fertilization, leading to a healthy birth post-prenatal diagnosis. A misdiagnosis of anaplastic anemia occurred in a family with multiple instances of Wiskott-Aldrich syndrome. A leukocyte adhesion deficiency type 1 case led to parental dissolution due to the father's refusal to acknowledge the condition. In a non-consanguineous couple, the father's diagnosis of TACI deficiency influenced the mother's decision to discontinue pregnancy post-prenatal diagnosis. Genetic diagnosis alone cannot optimize prenatal care for immune dysregulation disorders. Various factors, including patient education, societal norms, ethics, and economics, impact pregnancy decisions. Clinical immunologists must integrate these elements into guidance strategies to enhance patient outcomes.