ABSTRACT CTLA‐4 haploinsufficiency is caused by heterozygous variants in CTLA4. We report a cohort of five patients with a clinical presentation including immune dysregulation, hypogammaglobulinemia, lung damage, and gastrointestinal symptoms, consistent with CTLA‐4 haploinsufficiency. Patients ranged from 10 to 23 years of age, with three presenting before 7 years. Immunoglobulin levels and lymphocyte subpopulations were evaluated. All the patients evaluated showed low levels of CTLA‐4 and lymphoproliferation in unstimulated conditions. Treatment before genetic diagnosis consisted mainly of intravenous immunoglobulin replacement and pharmacological immunosuppression. Heterozygous variants in CTLA4 were detected by exome sequencing. Immunological evaluation revealed reduced CTLA‐4 expression and spontaneous lymphoproliferation. The identified heterozygous CTLA4 variants included two novel variants, one previously classified as likely pathogenic, one as pathogenic, and one as a variant of uncertain significance. These findings expand the spectrum of CTLA4 variants and support their clinical relevance.
López‐Herrera et al. (Tue,) studied this question.