Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
J Med Genet. 2013 Aug;50(8):500-6. doi: 10.1136/jmedgenet-2012-101152. Epub 2013 Apr 16.
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.
儿童期起病的肺动脉高压（PAH）较为罕见，其临床表现与成人起病的 PAH 不同，常伴有无法解释的智力迟钝和发育异常（MR/DF）。BMPR2 这一主要的 PAH 基因的突变被报道仅能导致 10-16%的儿童期起病的 PAH 患者发病。我们旨在确定更多与儿童期起病的 PAH 相关的基因。
我们研究了 20 例特发性或遗传性 PAH 连续病例。在伴有 MR/DF（n=6）的患者中进行了比较基因组杂交分析，旨在寻找包含 PAH 候选基因的常见缺失区域。有 3 例患者存在 17q23.2 的重叠缺失。从该区域中选择 TBX2 和 TBX4 作为候选基因，并对所有 20 例患儿进行测序。在这些患儿中发现 TBX4 突变后，我们随后对 49 例成人 PAH 患者进行了 TBX4 测序。因为 TBX4 突变已知会导致小髌骨综合征（SPS），所以所有新发现的 TBX4 突变患者均进行了 SPS 相关特征的筛查。我们还对第三个 23 例 SPS 患者队列进行了 PAH 筛查。
在 20 例 PAH 患儿中，检测到 6 例（30%）存在 TBX4 突变（n=3）或 TBX4 缺失（n=3）。所有存活的患儿和 2 例存在 TBX4 突变的父母似乎都存在先前未被识别的 SPS。在成人 PAH 患者队列中，检测到 1 例 TBX4 突变（2%）。对 SPS 患者队列（主要为成人）的筛查未发现 PAH。
这些数据表明，TBX4 突变与儿童期起病的 PAH 相关，但成年 TBX4 突变携带者中 PAH 的患病率较低。
