Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations.
Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations.
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DOI：
10.1002/ajmg.a.62584
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发表时间：
2022-03
影响因子：
2
通讯作者：
Shovlin, Claire L.
中科院分区：
文献类型：
--
作者：
Balachandar, Srimmitha;Graves, Tamara J.;Shimonty, Anika;Kerr, Katie;Kilner, Jill;Xiao, Sihao;Slade, Richard;Sroya, Manveer;Alikian, Mary;Curetean, Emanuel;Thomas, Ellen;McConnell, Vivienne P. M.;McKee, Shane;Boardman-Pretty, Freya;Devereau, Andrew;Fowler, Tom A.;Caulfield, Mark J.;Alton, Eric W.;Ferguson, Teena;Redhead, Julian;McKnight, Amy J.;Thomas, Geraldine A.;Aldred, Micheala A.;Shovlin, Claire L.
遗传性出血性毛细血管扩张症（HHT）是一种常染色体显性遗传的多系统性血管发育不良，以动静脉畸形（AVM）、粘膜皮肤毛细血管扩张和鼻出血为特征。HHT由ACVRL1、ENG或SMAD4中的杂合无效等位基因引起，其编码介导骨形态发生蛋白（BMP）信号传导的蛋白质。据报道，在GDF 2（编码BMP 9）中鉴定的几种错义和停止增益变体可导致类似于HHT的血管异常综合征，但这些患者均不符合HHT的诊断标准。来自英国NHS基因组医学中心的HHT家族被招募到基因组学英格兰100，000基因组项目。全基因组测序和分层方案在一个HHT家族的所有三个受影响成员中鉴定出一种新的杂合GDF 2序列变体，这些成员先前对ACVRL1、ENG和SMAD 4筛查为阴性。这三个人都有鼻出血和典型的HHT毛细血管扩张，先证者也有严重的肺AVM从童年。体外研究表明，突变体构建体表达前蛋白，但缺乏活性成熟BMP 9二聚体，表明突变破坏了蛋白质的正确切割。患者的血浆BMP 9水平显著低于对照组。总之，我们认为这种杂合子GDF2变异体是与肺AVM相关的HHT的罕见原因。
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant multisystemic vascular dysplasia, characterized by arteriovenous malformations (AVMs), mucocutaneous telangiectasia and nosebleeds. HHT is caused by a heterozygous null allele in ACVRL1, ENG, or SMAD4, which encode proteins mediating bone morphogenetic protein (BMP) signaling. Several missense and stop-gain variants identified in GDF2 (encoding BMP9) have been reported to cause a vascular anomaly syndrome similar to HHT, however none of these patients met diagnostic criteria for HHT. HHT families from UK NHS Genomic Medicine Centres were recruited to the Genomics England 100,000 Genomes Project. Whole genome sequencing and tiering protocols identified a novel, heterozygous GDF2 sequence variant in all three affected members of one HHT family who had previously screened negative for ACVRL1, ENG, and SMAD4. All three had nosebleeds and typical HHT telangiectasia, and the proband also had severe pulmonary AVMs from childhood. In vitro studies showed the mutant construct expressed the proprotein but lacked active mature BMP9 dimer, suggesting the mutation disrupts correct cleavage of the protein. Plasma BMP9 levels in the patients were significantly lower than controls. In conclusion, we propose that this heterozygous GDF2 variant is a rare cause of HHT associated with pulmonary AVMs.
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影响因子：
16.6
作者：
Gräf S;Haimel M;Bleda M;Hadinnapola C;Southgate L;Li W;Hodgson J;Liu B;Salmon RM;Southwood M;Machado RD;Martin JM;Treacy CM;Yates K;Daugherty LC;Shamardina O;Whitehorn D;Holden S;Aldred M;Bogaard HJ;Church C;Coghlan G;Condliffe R;Corris PA;Danesino C;Eyries M;Gall H;Ghio S;Ghofrani HA;Gibbs JSR;Girerd B;Houweling AC;Howard L;Humbert M;Kiely DG;Kovacs G;MacKenzie Ross RV;Moledina S;Montani D;Newnham M;Olschewski A;Olschewski H;Peacock AJ;Pepke-Zaba J;Prokopenko I;Rhodes CJ;Scelsi L;Seeger W;Soubrier F;Stein DF;Suntharalingam J;Swietlik EM;Toshner MR;van Heel DA;Vonk Noordegraaf A;Waisfisz Q;Wharton J;Wort SJ;Ouwehand WH;Soranzo N;Lawrie A;Upton PD;Wilkins MR;Trembath RC;Morrell NW
通讯作者：
Morrell NW
影响因子：
2
作者：
Rigelsky, Christina M.;Jennings, Constance;Aldred, Micheala A.
通讯作者：
Aldred, Micheala A.
影响因子：
168.9
作者：
Gallione, CJ;Repetto, GM;Marchuk, DA
通讯作者：
Marchuk, DA
纯合GDF2废话突变导致循环BMP9和BMP10损失，并且与儿童中的PAH或“ HHT样”综合征有关。
影响因子：
2
作者：
Hodgson J;Ruiz-Llorente L;McDonald J;Quarrell O;Ugonna K;Bentham J;Mason R;Martin J;Moore D;Bergstrom K;Bayrak-Toydemir P;Wooderchak-Donahue W;Morrell NW;Condliffe R;Bernabeu C;Upton PD
通讯作者：
Upton PD
影响因子：
64.8
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
通讯作者：
Hata, Akiko