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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
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  • UPENDRA MAHAT,
  • Nila Ambani,
  • seth rotz,
  • Kadakkal Radhakrishnan
UPENDRA MAHAT
Cleveland Clinic
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Nila Ambani
Cleveland Clinic
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seth rotz
Cleveland Clinic
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Kadakkal Radhakrishnan
Cleveland Clinic
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Abstract

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.