Heterozygous CTLA-4 splice site mutation c.458-1G>C presenting with variable degree of immune dysregulation and autoimmunity in three generation kindred of Caribbean descent

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an immune checkpoint, which downregulates T cell activation and T regulatory cell function. CTLA-4 haploinsufficiency (CTLA4 HI) leads to T cell hyperactivation, immune dysregulation, lymphoproliferation and cancer predisposition. Less well understood is the penetrance and expressivity of CTLA-4 mutations. We describe five members of a single family with heterozygous CTLA-4 splice site mutation c.458-1G>C, previously shown to result in CTLA-4 HI, who presented with variable degree of immune dysfunction, lymphocytic infiltration and autoimmunity. The host, environmental and the epigenetic factors affecting the penetrance and expressivity of CTLA-4 mutations merits further investigation.