hPAH transmits as an autosomal dominant trait that exhibits genetic anticipation but also markedly reduced penetrance.89, –91 Females with BMPR2 mutations have a higher disease penetrance and are about 2.5-fold more likely to develop hPAH than males.91 The cause of the reduced penetrance is likely to be related to a “second hit” caused by environmental and/or genetic modifiers. This evidence concerns the gene BMPR2 and heritable pulmonary arterial hypertension.