Vascular Malformations_Germline

Gene: GDF2

Green List (high evidence)

GDF2 (growth differentiation factor 2)
EnsemblGeneIds (GRCh38): ENSG00000263761
EnsemblGeneIds (GRCh37): ENSG00000128802
OMIM: 605120, Gene2Phenotype
GDF2 is in 7 panels

2 reviews

Bryony Thompson (Royal Melbourne Hospital)

Green List (high evidence)

4 probands/families with heterozygous variants with features of HHT and supporting in vitro or patient cell assays.
2 probands - PMID: 23972370 - first publication of the HHT gene-disease association describing 3 probands with 3 different missense variants & supporting in vitro functional assays. 1 of the missense variants is present in gnomAD v2.1 at a frequency not expected for the disease (p.Arg333Trp, 115 hets; p.Arg68Leu, 0 hets; p.Pro85Leu, 2 hets)
0 probands - PMID: 27081547 - a suspected HHT case with missense p.Arg317Gln, which is present in 11 hets in gnomAD v2.1
0 probands - PMID: 32573726 - identified 4 GDF2 variants (3 missense and 1 synonymous splice site adjacent without strong splice predictions) in a cohort of HHT cases, 3 had likely pathogenic/pathogenic ENG variants that could explain the phenotype, including a case with GDF2 p.Arg333Trp which was reported as pathogenic in the original publication from 2013
0 probands - PMID: 32992168 - a case with PAVM and no other features of HHT with a heterozygous missense (p.Gly291Ser), which is present in 20 hets in gnomAD v2.1.
1 family - PMID: 34611981 - a suspected HHT case and affected mother had heterozygous missense variant (p.Glu355Gln). Another suspected HHT case had another heterozygous missense variant (p.Val403Ile), but there are 23 hets in gnomAD v2.1. Also, 2 cases with multi-gene deletions including GDF2.
1 family - https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A6356 - A novel heterozygous GDF2 missense variant was identified in one HHT family from the 100,000 Genomes Project and segregated with disease. The proband was severely affected, having presented in childhood with multiple PAVMs, frequent epistaxis, and typical HHT telangiectasia. Plasma samples form the family showed significantly lower circulating BMP9 levels in affected cars compared to controls

3 homozygous cases with features of HHT, including PAVM:
2 probands - PMID: 33834622 - 2 unrelated paediatric cases with homozygous nonsense variants (p.Gln26Ter, p.Glu279Ter) with facial telangiectases and either pulmonary arterial hypertension or pulmonary arteriovenous malformations (PAVM). Plasma levels of both BMP9 and BMP10 were undetectable. Heterozygous parents did not have any symptoms or clinical signs of HHT.
1 proband - PMID: 32669404 - an 8 yo with epistaxis and diffuse PAVM homozygous for c.1060_1062delinsAG, p.Tyr354ArgfsTer15 (consanguineous family). 7 yo sister homozygous for the same variant had no symptoms, except some telangiectasia. Heterozygous parents had telangiectasia or epistaxis

2 supporting knockout animal models:
PMID: 26056270 - knockout mouse model had imperfect closure of ductus arteriosus (an arterial connection in the foetus that directs blood flow away from the pulmonary circulation)
PMID: 23972370 - BMP9 knockdown experiments in zebrafish exhibited small but significant decreases in both anterior-posterior and dorsal-ventral axes, as well as subtle defects in the maturation of the caudal vein.
Created: 18 Oct 2021, 1:28 a.m. | Last Modified: 18 Oct 2021, 1:28 a.m.
Panel Version: 1.4

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Telangiectasia, hereditary hemorrhagic, type 5 615506; pulmonary arteriovenous malformations

Publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Red List (low evidence)

Three unrelated individuals reported in the original publication. However note the population frequency of the variants is: Arg333Trp 115, Arg68Leu 13, and Pro85Leu 2, which casts doubt over their pathogenicity.
Created: 2 Jul 2020, 5:20 a.m. | Last Modified: 2 Jul 2020, 5:20 a.m.
Panel Version: 0.102

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Telangiectasia, hereditary hemorrhagic, type 5, MIM# 615506

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Royal Melbourne Hospital
Phenotypes
  • Telangiectasia, hereditary hemorrhagic, type 5 615506
  • pulmonary arteriovenous malformations
OMIM
605120
Clinvar variants
Variants in GDF2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

18 Oct 2021, Gel status: 3

Set Phenotypes

Bryony Thompson (Royal Melbourne Hospital)

Phenotypes for gene: GDF2 were changed from Telangiectasia, hereditary hemorrhagic, type 5 615506 to Telangiectasia, hereditary hemorrhagic, type 5 615506; pulmonary arteriovenous malformations

18 Oct 2021, Gel status: 3

Set publications

Bryony Thompson (Royal Melbourne Hospital)

Publications for gene: GDF2 were set to 23972370

18 Oct 2021, Gel status: 3

Set mode of inheritance

Bryony Thompson (Royal Melbourne Hospital)

Mode of inheritance for gene: GDF2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

18 Oct 2021, Gel status: 3

Entity classified by Genomics England curator

Bryony Thompson (Royal Melbourne Hospital)

Gene: gdf2 has been classified as Green List (High Evidence).

2 Jul 2020, Gel status: 1

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: gdf2 has been classified as Red List (Low Evidence).

2 Jul 2020, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: gdf2 has been classified as Amber List (Moderate Evidence).

2 Jul 2020, Gel status: 2

Set publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Publications for gene: GDF2 were set to

2 Jul 2020, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: gdf2 has been classified as Amber List (Moderate Evidence).

30 Dec 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Bryony Thompson (Royal Melbourne Hospital)

gene: GDF2 was added gene: GDF2 was added to Vascular Malformations_RMH. Sources: Expert Review Green,Royal Melbourne Hospital Mode of inheritance for gene: GDF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: GDF2 were set to Telangiectasia, hereditary hemorrhagic, type 5 615506