Memoona Shaukat (Heidelberg)1, E. Grünig (Heidelberg)1, S. Haas (Heidelberg)1, J. Haas (Heidelberg)2, M. Granzow (Heidelberg)3, T. Lange (Bad Reichenhall)4, S. Stadler (Regensburg)5, N. Sommer (Marburg)6, B. Meder (Heidelberg)7, S. Harutyunova (Heidelberg)1, B. Egenlauf (Heidelberg)1, P. Xanthouli (Heidelberg)1, K. Hinderhofer (Heidelberg)3, C. Eichstaedt (Heidelberg)1
1Center for Pulmonary Hypertension
Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital
Heidelberg, Deutschland; 2Institute for Cardiomyopathies Heidelberg
University Hospital Heidelberg, DZHK Site Heidelberg/Mannheim
Heidelberg, Deutschland; 3Institute of Human Genetics
Laboratory for Molecular Genetic Diagnostics
Heidelberg, Deutschland; 4Kreisklinik Bad Reichenhall
Department of Pneumology, Kliniken Südostbayern AG
Bad Reichenhall, Deutschland; 5Department of Internal Medicine II
Division of Pneumology, University Medical Center Regensburg
Regensburg, Deutschland; 6Department of Pneumology
Medical and Policlinic II, University Hospital of Gießen and Marburg
Marburg, Deutschland; 7Department of Internal Medicine III
Precision Digital Health, University of Heidelberg and Informatics for Life
Heidelberg, Deutschland
Hereditary pulmonary arterial hypertension (HPAH) is also defined as more than one affected family member with manifest PAH confirmed by right heart catheterization. HPAH is caused by mutations in at least one of 18 PAH genes known to date. However, there are still families with multiple affected members without a causative genetic variant in any of the known PAH genes. Hence, unknown genes and environmental factors may also contribute to PAH.
Objective: Our goal was to identify the genetic or environmental cause in HPAH families.
Methods: In 48 HPAH families PAH gene panel diagnostics using next-generation sequencing was performed for all known 18 genes. In families without a disease causing variant whole exome sequencing and assessment of further family members were performed. Questionnaires to investigate any drug intake or toxin exposure associated with PAH were obtained. Identified variants were characterized following ACMG guidelines.
Results: Out of 48 families 39 (81.3%) carried mutations in at least one of the 18 known PAH genes (Figure 1). Of the 9 remaining families, we performed in exome sequencing in five of them for 13 family members. In family 1, the mother was diagnosed aged 44 and her daughter aged 12 with HPAH. A novel deleterious missense variant in a not yet PAH associated TGF-beta signaling gene was identified. In family 2, both mother and daughter were diagnosed as adults with HPAH. Both had a new likely pathogenic splice site variant in a gene involved in angiogenesis and cell proliferation. In family 3, a deceased brother and the index patient were diagnosed with PAH and interstitial lung disease. The index patient carried a novel, likely pathogenic splice site variant in an interaction partner of the gene SOX17. The affected genes in family 1-3 are all potentially new PAH genes.
We could not find any genetic variant causative of HPAH in the remaining two families, but a common exposure to environmental factors. Family 4 had an affected father with severe idiopathic PAH and his son with a mild form of PAH and both had a long-term exposure to trichlorethylene solvent. In family 5, two siblings worked in a paint factory and both were diagnosed with a severe, rare form of PVOD. While exposure included toluene, xylene and aromatics, the precise causative agent remains to be determined.
Conclusions: Using PAH gene diagnostics panel, whole exome sequencing and assessment of family members we could identify mutations in 87.6% of HPAH families, in known genes in 81.3% and in one new not yet described TGF-beta-signaling protein and two other novel potential PAH genes in 3 families (6.3%). No further assessment was possible in 4 families (8.3%). However, in 2 families (4.2%) the familial aggregation of PAH was due to environmental toxin exposure rather than to genetic defects. Thus, it is essential to take all possible causes of PAH, including genetic and environmental factors, into account.