Hereditary haemorrhagic telangiectasia

Gene: GDF2

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 11:39 a.m. | Last Modified: 8 Mar 2022, 11:39 a.m.

Panel Version: 2.15

In PMID: 34904380 (Balachandar et al 2021) the authors state that the 3 related patients they report with a heterozygous variant in GDF2 are the first to meet the Curaçao criteria for Hereditary hemorrhagic telangiectas. (These patients were also reported in the conference abstract https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A6356).

Created: 20 Jan 2022, 4:57 p.m. | Last Modified: 20 Jan 2022, 4:57 p.m.

Panel Version: 2.11

Hernandez et al., 2015 (PMID: 27081547) identified a heterozygous GDF2 missense variant in an individual displaying features of HHT including epistaxis, telangiectasias, and PAVM. However, this was classified as a VUS due to a low population frequency of 0.05% in the 1000 Genomes (1/2,098 alleles) and 0.01% (1/13,006 alleles) in the ESP data set. No segregation or functional studies were performed.

3 individuals from a single family (2 sibs and mother) with HHT and a novel heterozygous GDF2 missense variant identified through the 100K Genomes Project. Functional studies showed the variant abrogates BMP9 expression (https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A6356).

Shovlin et al., 2020 (PMID: 32573726) identified GDF2 variants in 4 unrelated individuals with HHT but these were concurrent with likely pathogenic variants in ENG, and were therefore denoted as benign in the the context of these cases.

Liu et al., 2020 (PMID: 32669404) reported on a child with a homozygous frameshift GDF2 variant who presented with hypoxia and PAVMs but no cutaneous telangiectasias were detected. Parents were heterozygous carriers (single pinpoint-sized telangiectasia found on the mothers chest) but an asymptomatic sibling (except for a congenital dull purple vascular lesion on the forehead) harboured the same homozygous variant as the in the proband, suggesting reduced and/or age-related penetrance.

Hodgson et al., 2021 (PMID: 33834622) describe two paediatric patients homozygous for different GDF2 nonsense variants: one with PAH and the other with PAVMs; but both with facial telangiectases. Plasma levels of both BMP9 and BMP10 were undetectable in the index cases, which corresponded to low serum-derived endothelial BMP activity. Asymptomatic heterozygous parents had circulating levels below those of healthy controls, but serum activity was normal in one family.

Created: 27 Sep 2021, 3:08 p.m. | Last Modified: 27 Sep 2021, 3:08 p.m.

Panel Version: 2.7

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Telangiectasia, hereditary hemorrhagic, type 5, OMIM:615506

Publications

• 27081547
• 32573726
• 32669404
• 33834622
• https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A6356

I don't know

On CGGL Royal Brompton HHT diangostic panel. Limited evidence in literature, more required.

Created: 22 Sep 2019, 8:19 p.m. | Last Modified: 22 Sep 2019, 8:19 p.m.

Panel Version: 1.51

Phenotypes
OMIM: 615506 Telangiectasia, hereditary hemorrhagic, type 5

Publications

• 23972370
• 25674101

Variants in this GENE are reported as part of current diagnostic practice

I don't know

From GMS Respiratory Specialist Test Group webex call 18th Jan 2019 : keep classified as amber on basis of 3 cases (see review)

Created: 21 Jan 2019, 11:21 a.m.

Initial gene list and info collated by Ian Berry Leeds Genetics Laboratory November 2018 on behalf of the GMS Respiratory specialist test group. Gene Symbol submitted GDF2; Suggested initial gene rating: Green; Evidence for inclusion: OMIM HHT gene; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 6 Dec 2018, 12:36 p.m.

Comment on list classification: Discussed internally and decided to keep as amber as PMID:23972370 only provides evidence for inheritance in one proband. Awaiting more evidence for familial segregation.

Created: 14 Dec 2016, 11:30 a.m.

Comment on list classification: Changed status to amber due to the comment from reviewer that all variants reported are missense.

Created: 14 Dec 2016, 10:08 a.m.

I don't know

PMID: 34904380 reports a novel GDF2 variant (c.1282T>C, p.C428R) in three members of family displaying hereditary hemorrhagic telangiectasia (HHT) and pulmonary arteriovenous malformations. Functional studies support the delaterious effect of the variant in the normal cleavage of BMP9 proprotein, leading to an >2.5-fold lower level of the active mature dimer in the plasma of variant-positive family members in comparison to controls and lower levels of mature BMP9 from in vitro expression studies. There is phenotypic variability between patients carrying the same variant in HHT, and this is pronounced in the three cases reported in PMID: 34904380; although all of the cases in this familiy meet the Curaçao Criteria, the two non-proband cases are regarded as mild.

Created: 4 Jan 2022, 2:28 p.m. | Last Modified: 4 Jan 2022, 2:28 p.m.

Panel Version: 2.10

Comment on publications: 23972370 - 3 unrelated probands with no variants identified in ENG, ACVRL1, and SMAD4;27081547 - a variant of unknown significance in GDF2 was detected in one of 93 unrelated individuals clinically suspected to have HHT who previously tested negative for mutations in ENG, ACVRL1 and SMAD4;25674101 - review from the same authors as PMID:23972370

Created: 4 Jan 2022, 11:57 a.m. | Last Modified: 4 Jan 2022, 11:57 a.m.

Panel Version: 2.10

Comment when marking as ready: Associated with phenotype in OMIM, not in G2P / DD. At least four variants reported in cases, one of which is classified as a variant of unknown significance

Created: 13 Dec 2016, 12:19 p.m.

In vitro assays and zebra fish model evidence supports involvement of GDF2 in HHT, with variants having different effects

Created: 12 Dec 2016, 2:49 p.m.

Red List (low evidence)

The initial description was of novel pathogenic missense substitutions in three (of 191) unrelated patients clinically suspected to have hereditary haemorrhagic telangiectasia (HHT), but with no pathogenic variants identified in ENG, ACVRL1, or SMAD4 (PMID: 23972370). The three probands were considered to display some phenotypic overlap with HHT. A further missense substitution (assigned as a variant of unknown significance) was identified in a screen of 93 ENG, ACVRL1, and SMAD4 negative unrelated individuals clinically suspected to have HHT (PMID: 27081547).

HHT is usually caused by a pathogenic variant in either ENG or ACVRL1, with pathogenic missense substitutions more commonly found in ACVRL1. ExAc Constraint metrics [http://biorxiv.org/content/early/2016/05/10/030338 ] suggest GDF2 exhibits better toleration of missense substitutions than ACVRL1, and similar toleration to ENG: Missense GDF2 expected number of ExAc variants 165.7, observed 158, z=0.29 (contrast ACVRL1 expected 199.6, observed 132 z=2.34, but ENG expected 235.9, observed 223, z=0.41).

Created: 13 Nov 2016, 10:51 p.m.