Department of Pediatrics and Children's Research Institute, Milwaukee, WI, USA.
Eur J Hum Genet. 2012 Dec;20(12):1224-33. doi: 10.1038/ejhg.2012.80. Epub 2012 May 9.
Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.
眼前段发育不良 (ASD) 是一组广泛的影响眼前节结构的发育性疾病，与青光眼风险增加有关。Axenfeld-Rieger 综合征 (ARS) 和 De Hauwere 综合征等 ASD 病症常伴有各种系统性异常。我们对 76 例综合征或孤立性 ASD 及相关病症患者的 PITX2 和 FOXC1 进行了 DNA 测序和拷贝数分析。在所有患者中均发现存在牙齿和/或脐部异常的 24 例患者存在 PITX2 突变和缺失。所发现的 7 个 PITX2 突变等位基因均为新突变，包括迄今为止报告的最 C 端突变 c.708_730del。另一个 PITX2 远距离上游而非编码区缺失的病例被确定，突出了该新发现的 ARS 机制的重要性。FOXC1 缺失见于 4 例，其中 3 例伴有听力和/或心脏缺陷，包括一名患有 De Hauwere 综合征的患者；未在 FOXC1 中发现核苷酸突变。对文献的回顾确定了其他几位患有 6p25 缺失和 De Hauwere 综合征特征的患者。目前报告的 6p25 缺失 1.3 Mb 定义了该表型的关键区域，包括 FOXC1、FOXF2 和 FOXQ1 基因。综上所述，在我们的研究中，PITX2 或 FOXC1 破坏分别解释了 63%的 ARS 和 6%的其他 ASD；所有受影响的患者均表现出其他系统性缺陷，PITX2 突变与牙齿和/或脐部异常强相关，FOXC1 与心脏和听力缺陷相关。FOXC1 缺失也与 De Hauwere 综合征相关。
