The preponderance of genetic variations in paediatric pulmonary hypertension

OBJECTIVES: To determine the prevalence and phenotypes of children with heritable pulmonary arterial hypertension (PAH) and those with pulmonary hypertension (PH) associated with genetic disorders. METHODS: We retrospectively analysed 133 paediatric cases with PAH, with a median age of 6 years. RESULTS: 83 patients had isolated PAH, 41 had associated congenital heart disease, and 9 had suspected pulmonary veno occlusive disease. The female/male sex ratio was 1.8/1. Affected genes were BMPR2 [13], SOX17 [10], TBX4 [8], ACVRL1 [9], EIF2AK4 [4], GDF2 [2], BMP10 [1], and KCNK3 [1]. SOX17 variants were more common in children with APAH-CHD (p = 0.01). Additionally, 18% of patients had genetic disorders associated with PH, including Chuvash syndrome (n = 2), incontinentia pigmenti (n = 1), 5 patients with RASopathy (3 Noonan syndromes and 2 neurofibromatosis type 1), Cantu syndrome (n = 1), Alagille syndrome (n = 1), Bourneville tuberous sclerosis (n = 1), mitochondrial diseases (n = 5), Myhre syndrome (n = 1), and chromosomal rearrangements (n = 6). Overall, a significant proportion of patients had either pathogenic variants in known PAH genes or genetic disorders complicated by pulmonary vascular disease. CONCLUSION: The prevalence of genetic disorders and heritable PAH in children appears to be higher than previously reported, affecting over half of the paediatric population. This study emphasizes the importance of systematic genetic testing, including next-generation sequencing panels, in apparently idiopathic PAH and newly diagnosed PH patients. Larger genomic sequencing may be necessary to identify novel genes associated with these conditions when initial testing is negative.