Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension
| Autor: | Richard C. Trembath, Rolf M. F. Berger, Simone M. Gelinas, Clare E. Benson, Mohammed Athif Khan, Rajiv D. Machado, Laura Southgate |
|---|---|
| Přispěvatelé: | Cardiovascular Centre (CVC) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Candidate gene lung disease Disease 030204 cardiovascular system & hematology Bioinformatics Sulfonylurea Receptors Cohort Studies 0302 clinical medicine Risk Factors pulmonary arterial hypertension Epidemiology EPIDEMIOLOGY Child Genetics (clinical) Exome sequencing Adenosine Triphosphatases Platelet-Derived Growth Factor Lymphokines medicine.diagnostic_test Child Preschool Bone Morphogenetic Proteins Female medicine.medical_specialty lcsh:QH426-470 Genomics Article paediatrics 03 medical and health sciences Molecular genetics Genetics medicine Humans Genetic Predisposition to Disease Genetic testing business.industry MUTATIONS Infant Membrane Transport Proteins Genetic architecture BMP10 lcsh:Genetics 030104 developmental biology Smad8 Protein Mutation molecular genetics business exome sequencing GENOMICS |
| Zdroj: | Genes, 11(11):1328, 1-12. MDPI AG Genes Volume 11 Issue 11 Genes, Vol 11, Iss 1328, p 1328 (2020) |
| ISSN: | 2073-4425 |
| Popis: | Pulmonary arterial hypertension (PAH) describes a rare, progressive vascular disease caused by the obstruction of pulmonary arterioles, typically resulting in right heart failure. Whilst PAH most often manifests in adulthood, paediatric disease is considered to be a distinct entity with increased morbidity and often an unexplained resistance to current therapies. Recent genetic studies have substantially increased our understanding of PAH pathogenesis, providing opportunities for molecular diagnosis and presymptomatic genetic testing in families. However, the genetic architecture of childhood-onset PAH remains relatively poorly characterised. We sought to investigate a previously unsolved paediatric cohort (n = 18) using whole exome sequencing to improve the molecular diagnosis of childhood-onset PAH. Through a targeted investigation of 26 candidate genes, we applied a rigorous variant filtering methodology to enrich for rare, likely pathogenic variants. This analysis led to the detection of novel PAH risk alleles in five genes, including the first identification of a heterozygous ATP13A3 mutation in childhood-onset disease. In addition, we provide the first independent validation of BMP10 and PDGFD as genetic risk factors for PAH. These data provide a molecular diagnosis in 28% of paediatric cases, reflecting the increased genetic burden in childhood-onset disease and highlighting the importance of next-generation sequencing approaches to diagnostic surveillance. |
| Databáze: | OpenAIRE |
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