Study Expands Evidence of Inheritance Pattern in GDF2 Associated With PAH

Study results regarding the clinical spectrum and inheritance pattern of GDF2 pathogenic variants suggest incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance in the context of PAH.

A study focused on establishing a genetic diagnosis for pulmonary arterial hypertension (PAH) with overlapping hereditary hemorrhagic telangiectasia (HHT) features uncovered new evidence regarding the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants, according to findings published in Cells.

The study enrolled 2 index patients who were selected from the Spanish pediatric PAH registry. Family history was collected from the participants and DNA samples were collected from the proband and parents. Patient 1 was diagnosed with PAH associated with HHT at 5 years old, but neither of the parents presented PAH-suggestive symptoms nor was there any known family history of the disease. Patient 2 was diagnosed with idiopathic PAH (IPAH) at 4 years old, but none of her first-degree relatives showed any relevant symptoms for the disease.

After obtaining DNA from peripheral blood, genetic analysis was performed in the probands as well as on their parents. Samples were included into a customized next generation sequencing (NGS) panel of 21 genes (HAP v1.2) designed in-house, including: ACVRL1; GDF2; BMPR1B; BMPR2; CAV1; EIF2AK4; ENG; KCNA5; KCNK3; NOTCH3; SMAD1; SMAD4; SMAD5; SMAD9; TBX4; TOPBP1; SARS2; CPS1; ABCC8; CBLN2; MMACHC. Variant prioritization was performed and variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

All available first-degree relatives of the index case were analyzed and samples were obtained from the parents of the proband and siblings. The genetic segregation study was performed by sanger sequencing.

The study detected a homozygous missense variant in exon 1 of GDF in patient 1 (GDF2:NM_016204.4:c.328C > T:p.(Arg110Trp)), which causes a substitution of an arginine to tryptophan at amino acid position 110. Analysis showed that the parents and brother of the index patient were heterozygotes for the same variant, indicating that the child inherited a copy from each parent. When applying the ACMG criteria, this variant was classified as a likely pathogenic variant (LP).

Investigators detected a missense variant (GDF2:NM_016204.4:C.445G > A:p.(Glu149Lys)) in exon 2 of GDF2 in patient 2, and determined through variant segregation analysis that the variant was inherited from her mother. The study determined that the patient also inherited a deletion from her father of a size of 4.24 Mb located on chromosome 10, in the region q11.22-122.21, which includes 41 genes (AGAP4, FAM25E, PTPN20B, SYT15, GPRIN2, ANXA8L1, FAM25G, NPYAR, FAM25BP, AGAP10P, ANTXRL, ASAH2B, AGAP9, ANXA8, ZNF488, RBP3, GDF2, GDF10, FAM25C, FRMPD2, MAPK8, ARHGAP22, WDFYA, LRRC18, VSTM4, C10orf128, DRGX, ERCC6, CHAT, SLC18A3, OGDHL, PARG, AGAP7, TIM23, NOCOA4, MSMB, AGAP6, ASAH2), which included GDF2.

Although further research is needed, results of the study suggest that the presence of one of the variants is not enough for the development of PAH but that the presence of a second hit is necessary. Study results regarding the clinical spectrum and inheritance pattern of GDF2 pathogenic variants suggest incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.

The study suggests that variants in the GDF2 may lead to a greater disposition to develop both IPAH and a “HHT-like” syndrome, and that there is a wider range of inheritance patterns associated with GDF2 variants than previously believed. The results demonstrate the criticality of genetic counseling for families when planning future pregnancies or understanding the family history of the condition, study authors concluded.


Gallego N, Cruz-Utrilla A, Guillén I, Bonora AM, Ochoa N, Arias P, Lapunzina P, Escribano-Subias P, Nevado J, Tenorio-Castaño J. Expanding the evidence of a semi-dominant inheritance in GDF2 associated with pulmonary arterial hypertension. Cells. 2021; 10(11):3178. doi:10.3390/cells10113178