The Experience of a Tertiary Reference Center in Central Anatolia with Children Carrying ZAP-70 Variants, Including Two Novel Variants.

purposeZeta-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.

methodsThis 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.

resultsAmong 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.

conclusionThis 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.