Monogenic disorders of immunity: Common variants are not so rare

According to the current paradigm, human monogenic disorders underlying immunological phenotypes are due to rare (frequency 1%) alleles. However, as reviewed here, an increasing number of studies have reported monogenic disorders of immunity, recessive or dominant, involving alleles that are currently common in specific small or large populations. Examples range from IFNAR1 and IFNAR2 null alleles in the Arctic and Pacific to PTCRA hypomorphic alleles in South Asia. This situation may be explained by a history of (1) population bottlenecks followed by expansion; (2) genetic drift before the advent of an environmental trigger; (3) slow purging, especially for recessive, mild, or incompletely penetrant conditions; and/or (4) balancing selection with a heterozygous advantage. In patients with suspected monogenic immunological conditions, a role for alleles common in the corresponding population should not be excluded. At odds with the prevailing view, common alleles may underlie monogenic disorders of immunity and should therefore be considered.