Clinical, immunologic and genetic characteristics of 148 patients with NK cell deficiency.

Abstract

Background: Natural killer (NK) cell deficiency (NKD) is an immunodeficiency phenotype in which abnormality of NK cells is the major clinically relevant immune defect.

Objective: We sought to define the clinical, immunologic and genetic characteristics of patients with NKD to aid in the understanding of these individuals and this cell type, and guide future research and clinical practice.

Methods: During 2006-2022, 168 individuals suspected of having NKD were enrolled, with comprehensive clinical, immunological and genetic data collected and analyzed. Research exome sequencing was performed to identify both known and novel genetic associations.

Results: NK cell abnormalities consistent with NKD were confirmed in 148 individuals. Most presented during childhood (median age 13y, range 0-76y), though 34% were adults. All tested individuals exhibited reduced NK cell cytotoxic function; 44% also had decreased NK cell numbers and/or mature NK cells. Herpesvirus and/or papillomavirus infections were observed in 71%, malignancies in 7%, and a 5% case-fatality rate was noted. Among the 99 individuals who underwent research exome sequencing, 29% were considered solved for a likely contributing variant allele, 52% of these cases involving known genes and 48% involving novel genes.

Conclusions: NKD is a phenotypic immunodeficiency associated with increased susceptibility to certain viral infections and cancer, with multiple genetic etiologies, revealing key biological pathways for NK cell development and function. This research underscores the role of NK cells in human immune defenses, and helps advance the identification of at-risk populations, precise genetic diagnoses, and informed clinical management for those with NKD.