Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Nov 15;10(11):3178.
doi: 10.3390/cells10113178.

Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Natalia Gallego  1   2   3 , Alejandro Cruz-Utrilla  4   5 , Inmaculada Guillén  6 , Amparo Moya Bonora  7 , Nuria Ochoa  4   5 , Pedro Arias  1   2   3 , Pablo Lapunzina  1   2   3 , Pilar Escribano-Subias  4   5   8 , Julián Nevado  1   2   3 , Jair Tenorio-Castaño  1   2   3
Affiliations

Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Natalia Gallego et al. Cells. .

Abstract

Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes ACVRL1, ENG, SMAD4 and GDF2 can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in GDF2 in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.

Keywords: GDF2; NGS; genomic medicine; hereditary hemorrhagic telangiectasia; massive parallel sequencing; personalized medicine; pulmonary arterial hypertension.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Filtering pipeline for NGS panel HAP v1.2. Modified from Tenorio et al. 2020 [25].
Figure 2
Figure 2
Pedigree of both families with GDF2 variants. Segregation analysis of GDF2 in all available family members. The figure shows a fragment of the GDF2 sequence with corresponding amino acids below. (A) Patient 1: It represents the homozygous missense variant at nucleotide position c.328 (c.328C > T) in exon 1 of GDF2 (NM_016204.3), which causes the amino acid substitution arginine to tryptophane at peptide position 110 (p.Arg110Trp) in the index patient. In addition, it shows the same heterozygous missense variant found in healthy parents and brother. (B) Patient 2: The missense variant at nucleotide position c.445 in exon 2 of GDF2 (NM_ 016204.4), which causes the amino acid substitution glutamine to lysine at peptide position 149 in the index patient and mother and the deletion inherited from her father. Double line denotes consanguinity. Legend: +/+ homozygous for the alternative allele; +/− heterozygous for the alternative allele; del: deletion.
Figure 3
Figure 3
Resolution of the SNP array carried out in proband 2 and family members showing the 4.2 Mb deletion in q11.22−q11.23 region of chromosome 10 (in orange).
See this image and copyright information in PMC

References

    1. Simonneau G., Montani D., Celermajer D.S., Denton C.P., Gatzoulis M.A., Krowka M., Williams P.G., Souza R. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. J. 2019;53:1801913. doi: 10.1183/13993003.01913-2018. - DOI - PMC - PubMed
    1. Galiè N., Humbert M., Vachiery J., Gibbs S., Lang I., Torbicki A., Simonneau G., Peacock A., Vonk Noordegraaf A., Beghetti M. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT) Eur. Heart J. 2016;37:67–119. - PubMed
    1. Machado R.D., Eickelberg O., Elliott C.G., Geraci M.W., Hanaoka M., Loyd J.E., Newman J.H., Phillips J.A., Soubrier F., Trembath R.C. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 2009;54:S32–S42. doi: 10.1016/j.jacc.2009.04.015. - DOI - PMC - PubMed
    1. Deng Z., Morse J.H., Slager S.L., Cuervo N., Moore K.J., Venetos G., Kalachikov S., Cayanis E., Fischer S.G., Barst R.J. Familial primary pulmonary hypertension (Gene PPH1) is caused by mutations in the bone morphogenetic protein receptor–II gene. Am. J. Hum. Genet. 2000;67:737–744. doi: 10.1086/303059. - DOI - PMC - PubMed
    1. Lane K.B., Machado R.D., Pauciulo M.W., Thomson J.R., Phillips J.A., Loyd J.E., Nichols W.C., Trembath R.C. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. Nat. Genet. 2000;26:81–84. doi: 10.1038/79226. - DOI - PubMed

Publication types

Substances