The cascade screening in heritable forms of pulmonary arterial hypertension

Abstract

Heritable pulmonary artery hypertension (HPAH) is an increasingly recognized type of pulmonary arterial hypertension, in both pediatric and adult population. Intrinsic to hereditary disease, screening for genetic mutations within families is an important component of diagnosis and understanding burden of disease. Recently, consensus guidelines are published for genetic screening in PAH. These guidelines include recommendations for screening at diagnosis, noting individuals with presumed PAH due to familial, or idiopathic etiologies. Cascade genetic testing is specifically recommended as a testing paradigm to screen relatives for detection of mutation carriers, who may be asymptomatic. Without targeted genetic testing, familial mutation carriers may only come to attention when pulmonary vascular disease burden is high enough to cause symptoms, suggesting more advanced disease. Here, we present our collective experience with HPAH in five distinct families, specifically to report on the clinical courses of patients who were diagnosed with genetic mutation at diagnosis versus those who were offered genetic screening. In three families, asymptomatic mutation carriers were identified and monitored for clinical worsening. In two families, screening was not done and affected family members presented with advanced disease.

Keywords: BMPR2 mutation; cascade testing; genetics; heritable pulmonary arterial hypertension; screening.

Figure 1

Representative family pedigree of Case 3. Pediatric patient (child) diagnosed in 2018; parental testing declined. Cascade testing not done. Father of proband diagnosed in 2020. Cascade testing not done. Brother of father (paternal uncle of proband) diagnosed in 2021. At that time, cascade testing was done and revealed same pathogenic mutation in proband and one child.