CTLA4 and Down syndrome: While historically large pedigrees were necessary to identify novel causative gene defects and the majority of identified defects were inherited in an autosomal recessive manner (in part because studies in consanguineous pedigrees were used to identify underlying gene defects), more recently, an increasing number of autosomal dominant (AD) PIDs has been discovered, including such that work through AD gain-of-function mutations (e.g., activated PIK3δ syndrome [21–24]) or haploinsufficiency (e.g., CTLA4 haploinsufficiency syndrome [25, 26]).