TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension.
TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension.
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DOI：
10.1136/jmedgenet-2012-101152
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发表时间：
2013-08
影响因子：
4
通讯作者：
Berger RM
中科院分区：
文献类型：
--
作者：
Kerstjens-Frederikse WS;Bongers EM;Roofthooft MT;Leter EM;Douwes JM;Van Dijk A;Vonk-Noordegraaf A;Dijk-Bos KK;Hoefsloot LH;Hoendermis ES;Gille JJ;Sikkema-Raddatz B;Hofstra RM;Berger RM
儿童期发作的肺动脉高压（PAH）是一种罕见的疾病，其临床表现与成人期发作的疾病不同，通常伴有不明原因的智力低下和畸形特征（MR/DF）。据报道，主要PAH基因BMPR 2突变仅在10-16%的儿童期发病患者中引起PAH。我们的目的是确定更多的基因与儿童期发作的PAH。我们研究了20例特发性或遗传性PAH的连续病例。在伴有MR/DF的患者（n=6）中，进行了阵列比较基因组杂交分析，目的是找到含有PAH候选基因的共同缺失区域。3例患者有17q23.2重叠缺失。从该地区选择TBX 2和TBX 4作为候选基因，并对所有20名儿童进行测序。在这些儿童中鉴定出TBX 4突变后，我们随后对49名PAH成人的TBX 4进行了测序。由于已知TBX 4突变会导致小髌骨综合征（SPS），因此对所有新检测到TBX 4突变的患者进行SPS特征筛查。我们还对第三组23例SPS患者进行了PAH筛查。20例PAH患儿中有6例（30%）检测到TBX 4突变（n=3）或含TBX 4缺失（n=3）。所有存活的患者和两名携带TBX 4突变的父母似乎都患有以前未识别的SPS。在成人PAH队列中，检测到1个TBX 4突变（2%）。在SPS患者（主要是成人）队列中进行的筛选显示无PAH。这些数据表明TBX 4突变与儿童期发作的PAH相关，但成年TBX 4突变携带者中PAH的患病率较低。
Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene, BMPR2, were reported to cause PAH in only 10–16% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH. We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2. TBX2 and TBX4 were selected from this area as candidate genes and sequenced in all 20 children. After identifying TBX4 mutations in these children, we subsequently sequenced TBX4 in a cohort of 49 adults with PAH. Because TBX4 mutations are known to cause small patella syndrome (SPS), all patients with newly detected TBX4 mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH. TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with TBX4 mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one TBX4 mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH. These data indicate that TBX4 mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult TBX4 mutation carriers is low.
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影响因子：
3.6
作者：
Grünig, E;Koehler, R;Janssen, B
通讯作者：
Janssen, B
影响因子：
168.9
作者：
Berger, Rolf M. F.;Beghetti, Maurice;Humpl, Tilman;Raskob, Gary E.;Ivy, D. Dunbar;Jing, Zhi-Cheng;Bonnet, Damien;Schulze-Neick, Ingram;Barst, Robyn J.
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Barst, Robyn J.
影响因子：
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Aldred, Micheala A.;Vijayakrishnan, Jairam;Trembath, Richard C.
通讯作者：
Trembath, Richard C.
影响因子：
3.9
作者：
Nasim, Md. Talat;Ogo, Takeshi;Machado, Rajiv D.
通讯作者：
Machado, Rajiv D.
影响因子：
2.5
作者：
Cebra-Thomas, JA;Bromer, J;Gilbert, SF
通讯作者：
Gilbert, SF