An ancient founder mutation located between ROBO1 and ROBO2 is responsible for increased microtia risk in Amerindigenous populations

Abstract

Significance The genetic basis of isolated microtia, a congenital abnormality of the external ear, is poorly understood. Indigenous American (Amerindigenous) populations have the highest reported incidence of microtia. Here, we use whole genome sequencing to study microtia in Latin American families and identify a common microtia risk allele that is enriched among individuals with Amerindigenous ancestry. This allele is located in a regulatory region governing the expression of Roundabout 1 ( ROBO1 ) and Roundabout 2 ( ROBO2 ) in induced pluripotent stem cell–derived neural crest cells and is associated with a complex repeat sequence. These results identify a shared genetic basis for isolated microtia and other craniofacial abnormalities and account for, at least in part, the increased incidence of microtia in Amerindigenous populations.