Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Moorfields Eye Hospital, London, UK.
Acta Ophthalmol. 2022 Jun;100(4):431-439. doi: 10.1111/aos.15022. Epub 2021 Oct 13.
The aim of the study was to describe the phenotype and molecular genetic causes of X-linked megalocornea (MGC1). We recruited four British, one New Zealand, one Vietnamese and four Czech families.
All probands and three female carriers underwent ocular examination and Sanger sequencing of the CHRDL1 gene. Two of the probands also had magnetic resonance imaging (MRI) of the brain.
We identified nine pathogenic or likely pathogenic and one variant of uncertain significance in CHRDL1, of which eight are novel. Three probands had ocular findings that have not previously been associated with MGC1, namely pigmentary glaucoma, unilateral posterior corneal vesicles, unilateral keratoconus and unilateral Fuchs heterochromic iridocyclitis. The corneal diameters of the three heterozygous carriers were normal, but two had abnormally thin corneas, and one of these was also diagnosed with unilateral keratoconus. Brain MRI identified arachnoid cysts in both probands, one also had a neuroepithelial cyst, while the second had a midsagittal neurodevelopmental abnormality (cavum septum pellucidum et vergae).
The study expands the spectrum of pathogenic variants and the ocular and brain abnormalities that have been identified in individuals with MGC1. Reduced corneal thickness may represent a mild phenotypic feature in some heterozygous female carriers of CHRDL1 pathogenic variants.
本研究旨在描述 X 连锁型巨角膜（MGC1）的表型和分子遗传病因。我们招募了四个英国家庭、一个新西兰家庭、一个越南家庭和四个捷克家庭。
所有先证者和三位女性携带者均接受了眼部检查和 CHRDL1 基因的 Sanger 测序。两位先证者还接受了脑部磁共振成像（MRI）检查。
我们在 CHRDL1 中发现了九个致病性或可能致病性的变异和一个意义不明的变异，其中有八个是新的。三位先证者存在以前与 MGC1 无关的眼部表现，即色素性青光眼、单侧后角膜囊泡、单侧圆锥角膜和单侧 Fuchs 异色性虹膜炎。三位杂合子携带者的角膜直径正常，但有两位角膜异常变薄，其中一位还被诊断为单侧圆锥角膜。脑部 MRI 发现两位先证者均存在蛛网膜囊肿，其中一位还存在神经上皮囊肿，而第二位存在中线神经发育异常（透明隔腔及穹窿缺如）。
本研究扩展了 MGC1 患者中已确定的致病性变异以及眼部和脑部异常的范围。在 CHRDL1 致病性变异的某些杂合子女性携带者中，角膜变薄可能代表一种轻度的表型特征。
