Abstract：
Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) may be misdiagnosed as primary congenital glaucoma (PCG) due to similar clinical phenotypes during early infancy. In this study, we identified a family with CHED2, which was previously misdiagnosed as having PCG, and followed up for 9 years. Linkage analysis was first completed in eight PCG-affected families, followed by whole-exome sequencing (WES) in family PKGM3. The following in silico tools were used to predict the pathogenic effects of identified variants: I-Mutant 2.0, SIFT, Polyphen-2, PROVEAN, mutation taster and PhD-SNP. After detecting an SLC4A11 variant in one family, detailed ophthalmic examinations were performed again to confirm the diagnosis. Six out of eight families had CYP1B1 gene variants responsible for PCG. However, in family PKGM3, no variants in the known PCG genes were identified. WES identified a homozygous missense variant c.2024A>C, p.(Glu675Ala) in SLC4A11. Based on the WES findings, the affected individuals underwent detailed ophthalmic examinations and were re-diagnosed with CHED2 leading to secondary glaucoma. Our results expand the genetic spectrum of CHED2. This is the first report from Pakistan of a Glu675Ala variant with CHED2 leading to secondary glaucoma. The p.Glu675Ala variant is likely a founder mutation in the Pakistani population. Our findings suggest that genome-wide neonatal screening is worthwhile to avoid the misdiagnosis of phenotypically similar diseases such as CHED2 and PCG.
摘要：
常染色体隐性遗传先天性遗传性内皮营养不良（CHED2）在婴儿期早期可能由于相似的临床表型而被误诊为原发性先天性青光眼（PCG）。在这项研究中,我们确定了一个患有CHED2的家庭，该家庭先前被误诊为患有PCG，并随访了9年。连锁分析首先在八个受PCG影响的家庭中完成，其次是家族PKGM3的全外显子组测序（WES）。以下模拟工具用于预测已识别变体的致病作用：I-Mutant2.0，SIFT，Polyphen-2,PROVEAN,突变品尝者和博士SNP。在检测到一个家族中的SLC4A11变体后，再次进行详细的眼科检查以确认诊断.八个家族中有六个具有负责PCG的CYP1B1基因变体。然而,在家族PKGM3中,未发现已知PCG基因的变异体.WES鉴定出纯合错义变体c.2024A>C，p.（Glu675Ala）在SLC4A11。根据WES的调查结果，受影响的个体接受了详细的眼科检查,并再次诊断为CHED2,导致继发性青光眼.我们的成果扩大了CHED2的遗传谱。这是巴基斯坦首次报道的Glu675Ala变体与CHED2导致继发性青光眼。p.Glu675Ala变体可能是巴基斯坦人口中的创始人突变。我们的发现表明，全基因组新生儿筛查对于避免表型相似疾病如CHED2和PCG的误诊是值得的。
