Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Curr Eye Res. 2020 Jan;45(1):91-96. doi: 10.1080/02713683.2019.1649704. Epub 2019 Aug 14.
: Aniridia is a rare congenital eye disease, characterized by a constellation of symptoms including hypoplastic irides, foveal hypoplasia, early cataract, corneal stem cell deficiency, and glaucoma. Large chromosomal deletions spanning the gene cause WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability [formerly called mental retardation]). We describe clinical and genetic studies of a three-generation pedigree with aniridia along with additional systemic conditions (morbid obesity, diabetes) suggesting the possibility of a contiguous-gene syndrome like WAGR.: Clinical records were obtained and DNA was prepared from blood samples from three of the four patients and tested for mutations in the coding sequences of the gene. The index patient also had cardiomyopathy and was tested for known cardiomyopathy genetic mutations using a next-generation DNA sequencing assay.: We discovered a novel intragenic mutation, a 16 bp heterozygous deletion c.203delCCAGGGCAATCGGTGG, with Sanger sequencing that is the likely cause of autosomal dominant aniridia in this pedigree. This deletion causes a frameshift in predicted protein translation and a subsequent premature termination, p.Pro68Leufs*6. The deletion was detected in all three available family members with aniridia, the index patient, his mother, and his maternal aunt but was not observed in the ome ggregation onsortium (ExAC) database. Targeted sequencing of known cardiomyopathy genes in the index patient identified a second mutation, a 1.7 Mp deletion that spans the gene.: We report a pedigree with aniridia and other systemic abnormalities that were initially suspicious for a contiguous-gene syndrome like WAGR. However, genetic analysis of the pedigree revealed two independent genetic abnormalities on chromosome 11p: 1) a novel mutation, and 2) a large chromosome deletion spanning , a known cardiomyopathy gene. It is unclear if morbid obesity and type II diabetes mellitus have a related genetic cause.
先天性虹膜缺失症是一种罕见的眼部疾病，其特征是多种症状并存，包括虹膜发育不全、中心凹发育不良、早发性白内障、角膜干细胞缺乏和青光眼。跨越 基因的大片段染色体缺失导致 WAGR 综合征（Wilms 瘤、先天性虹膜缺失、泌尿生殖系统异常和智力障碍[以前称为智力迟钝]）。我们描述了一个三代家系的临床和遗传学研究，该家系患有先天性虹膜缺失症，以及其他全身疾病（病态肥胖、糖尿病），提示存在类似于 WAGR 的连续基因综合征的可能性：临床记录是从四个患者中的三个患者的血液样本中获得的，并测试了 基因编码序列中的突变。索引患者还患有心肌病，并使用下一代 DNA 测序分析测试了已知的心肌病基因突变：我们发现了一个新的基因内 突变，一个 16 个碱基对的杂合缺失 c.203delCCAGGGCAATCGGTGG，使用 Sanger 测序，这可能是该家系常染色体显性遗传先天性虹膜缺失的原因。该缺失导致预测蛋白翻译中的移码和随后的提前终止，p.Pro68Leufs*6。在所有三个可获得的具有先天性虹膜缺失症的家族成员中，即索引患者、他的母亲和他的姨母中检测到 缺失，而在对照群体（ExAC）数据库中未观察到。在索引患者中已知的心肌病基因的靶向测序中鉴定出第二个突变，一个跨越 基因的 1.7 Mb 缺失：我们报告了一个具有先天性虹膜缺失症和其他全身异常的家系，最初怀疑是类似于 WAGR 的连续基因综合征。然而，对家系的遗传分析显示 11p 染色体上存在两个独立的遗传异常：1）一个新的 突变，和 2）跨越 的大片段染色体缺失，已知的心肌病基因。病态肥胖和 2 型糖尿病是否有相关的遗传原因尚不清楚。
