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

TL;DR

This study reports on children with ZAP-70 deficiency, including two new genetic variants, and highlights the importance of functional analysis for diagnosis and treatment.

Contribution

The study identifies two novel ZAP70 variants and emphasizes functional analysis for variant classification in ZAP-70 deficiency.

Findings

Two previously unreported ZAP70 variants were identified in patients with ZAP-70 deficiency.

Functional analyses showed impaired TCR signaling and reduced IL-2 production in patients with novel variants.

Clinical outcomes varied widely, even among siblings with the same variant, suggesting genetic or environmental modifiers.

Abstract

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.

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