Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension.
Activin Receptors, Type II
/ genetics
Adenosine Triphosphatases
/ genetics
Familial Primary Pulmonary Hypertension
/ diagnosis
Genetic Predisposition to Disease
/ genetics
Humans
Hypertension, Pulmonary
/ diagnosis
Membrane Transport Proteins
/ genetics
Mutation
/ genetics
Protein Serine-Threonine Kinases
Pulmonary Arterial Hypertension
/ diagnosis
Bi-allelic variants
Gene panel diagnostics
Genetic testing
Pulmonary arterial hypertension
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
27 Mar 2022
27 Mar 2022
Historique:
received:
23
10
2021
accepted:
14
03
2022
entrez:
29
3
2022
pubmed:
30
3
2022
medline:
5
4
2022
Statut:
epublish
Résumé
A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years. Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery. A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH. Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.
Sections du résumé
BACKGROUND
BACKGROUND
A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years.
METHODS
METHODS
Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery.
RESULTS
RESULTS
A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH.
CONCLUSIONS
CONCLUSIONS
Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes.
Identifiants
pubmed: 35346192
doi: 10.1186/s12931-022-01987-x
pii: 10.1186/s12931-022-01987-x
pmc: PMC8962083
doi:
Substances chimiques
Membrane Transport Proteins
0
EIF2AK4 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
ACVRL1 protein, human
EC 2.7.11.30
Activin Receptors, Type II
EC 2.7.11.30
ATP13A3 protein, human
EC 3.6.1.-
Adenosine Triphosphatases
EC 3.6.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
74Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : 268555672 - SFB A1213
Organisme : Deutsche Forschungsgemeinschaft
ID : 268555672 - SFB A1213
Organisme : Bundesministerium für Bildung und Forschung
ID : 01EO1503
Informations de copyright
© 2022. The Author(s).
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