Genetic counselling in a national referral centre for pulmonary hypertension

Abstract

Genetic causes of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) have been identified, leading to a growing need for genetic counselling.Between 2003 and 2014, genetic counselling was offered to 529 PAH and 100 PVOD patients at the French Referral Centre for Pulmonary Hypertension.Mutations in PAH-predisposing genes were identified in 72 patients presenting as sporadic PAH (17% of cases; 62 mutations in BMPR2, nine in ACVRL1 (ALK1) and one in ENG) and in 94 patients with a PAH family history (89% of cases; 89 mutations in BMPR2, three in ACVRL1 (ALK1) and two in KCNK3). Bi-allelic mutations in EIF2AK4 were identified in all patients with a family history of PVOD (n=19) and in seven patients (8.6%) presenting as sporadic PVOD. Pre-symptomatic genetic diagnosis was offered to 272 relatives of heritable PAH patients, identifying mutations in 36.4% of them. A screening programme is now offered to asymptomatic mutation carriers to detect PAH in an early phase and to identify predictors of outcomes in asymptomatic BMPR2 mutation carriers. BMPR2 screening allowed us to offer pre-implantation diagnosis to two couples with a BMPR2 mutation.Genetic counselling can be implemented in pulmonary hypertension centres.@ERSpublications Genetic causes of PAH and PVOD have been identified; genetic counselling can be implemented in PH centres

Heritable pulmonary hypertension: from bench to bedside

“…In addition, genetic counselling and testing were offered to 100 PVOD/PCH patients. Bi-allelic mutations in the EIF2AK4 gene were identified in all PVOD/PCH patients with a familial form of the disease (n=19) and in seven (9%) patients presenting with a sporadic form of PVOD/PCH [49].…”

“…In a study from the French PAH referral centre, 272 adult relatives requested predictive testing for PAH, in whom we identified 99 (36%) asymptomatic carriers of PAH-predisposing mutations (96 carriers of a BMPR2 mutation, one carrier of an ACVRL1 mutation and two carriers of a KCNK3 mutation [49]. The risk of developing PAH is estimated to be 14% for males and 42% for females among such individuals with predisposing mutations [38].…”

“…A mutation was identified in 72 (17%) sporadic PAH patients (n=62 in BMPR2, n=9 in ACVRL1 and n=1 in endoglin) and in 89% of patients displaying a familial form of PAH (n=89 BMPR2 mutations, n=3 ACVRL1 mutations and n=2 KCNK3 mutations). No mutations were identified in 11% of patients with a family history of PAH (figure 2) [49]. In addition, genetic counselling and testing were offered to 100 PVOD/PCH patients.…”

“…Counselling for PAH and PVOD/PCH patients The establishment of a genetic counselling programme in France (at the French PAH referral centre, Hôpital Bicêtre, Le Kremlin-Bicêtre and at Hôpital Necker Enfants Malades, Paris), enables us to offer genetic screening to all patients with familial and sporadic PAH or PVOD/PCH and to patients with drug and toxin-induced PAH or PVOD/PCH [49]. Genetic analyses using next-generation sequencing are performed in the oncogenetics and angiogenetics laboratory at Hôpital Pitié Salpêtrière (Paris).…”

“…Candidate genes in this region were then identified and mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene were found in PAH patients (figure 1) [5,6]. Additional genetic analyses revealed that 3.5-40% of sporadic PAH patients [7][8][9][10][11][12][13] and 9-22.5% of anorexigen-associated PAH patients carried a mutation in this main gene [14,15].…”