Seifi Morteza, Footz Tim, Taylor Sherry A M, Elhady Ghada M, Abdalla Ebtesam M, Walter Michael A
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Acta Ophthalmol. 2016 Nov;94(7):e571-e579. doi: 10.1111/aos.13030. Epub 2016 Mar 24.
Mutations in the bicoid-like transcription factor PITX2 gene often result in Axenfeld-Rieger syndrome (ARS), an autosomal-dominant inherited disorder. We report here the discovery and characterization of novel PITX2 deletions in a small kindred with ARS.
Two familial patients (father and son) from a consanguineous family were examined in the present study. Patient DNA samples were screened for PITX2 mutations by DNA sequencing and for copy number variation by SYBR Green quantitative polymerase chain reaction (PCR) analysis.
We report a novel deletion involving the coding region of PITX2 in both patients. The minimum size of the deletion is 1 421 914 bp that spans one upstream regulatory element (CE4), PITX2 and a minimum of 13 neighbouring genes. The maximum size of the deletion is 3 789 983 bp. The proband (son) additionally possesses a novel 2-bp deletion in a non-coding exon of the remaining PITX2 allele predicted to alter correct splicing.
Our findings implicate a novel deletion of the PITX2 gene in the pathogenesis of ARS in the affected family. This ARS family presented with an atypical and extremely severe phenotype that resulted in four miscarriages and the death at 10 months of age of a sib of the proband. As the phenotypic manifestations in the proband are more severe than that of the father, we hypothesize that the deletion of the entire PITX2 allele plus a novel 2-bp deletion (observed in the proband) within the remaining PITX2 allele together contributed to the atypical ARS presentation in this family. This is the first study reporting on bi-allelic changes of PITX2 potentially contributing to a more severe ARS phenotype.
类双尾状转录因子PITX2基因的突变常导致常染色体显性遗传性疾病Axenfeld-Rieger综合征（ARS）。我们在此报告在一个患有ARS的小家族中发现并鉴定了新型PITX2缺失。
本研究检测了来自一个近亲家族的两名家族性患者（父子）。通过DNA测序筛查患者DNA样本中的PITX2突变，并通过SYBR Green定量聚合酶链反应（PCR）分析检测拷贝数变异。
我们报告在两名患者中均发现了涉及PITX2编码区的新型缺失。该缺失的最小大小为1421914 bp，跨越一个上游调控元件（CE4）、PITX2以及至少13个相邻基因。缺失的最大大小为3789983 bp。先证者（儿子）在剩余PITX2等位基因的一个非编码外显子中还存在一个新型的2 bp缺失，预计会改变正确的剪接。
我们的研究结果表明，受影响家族中ARS的发病机制与PITX2基因的新型缺失有关。这个ARS家族表现出非典型且极其严重的表型，导致四次流产以及先证者的一个兄弟姐妹在10个月大时死亡。由于先证者的表型表现比父亲更严重，我们推测整个PITX2等位基因的缺失加上剩余PITX2等位基因中一个新型的2 bp缺失（在先证者中观察到）共同导致了该家族中ARS的非典型表现。这是第一项报道PITX2双等位基因变化可能导致更严重ARS表型的研究。
