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Abstract：
Childhood glaucoma (CG) encompasses a heterogeneous group of genetic eye disorders that is responsible for approximately 5% of childhood blindness worldwide. Understanding the molecular aetiology is key to improving diagnosis, prognosis and unlocking the potential for optimising clinical management. In this study, we investigated 86 CG cases from 78 unrelated families of diverse ethnic backgrounds, recruited into the Genomics England 100,000 Genomes Project (GE100KGP) rare disease cohort, to improve the genetic diagnostic yield. Using the Genomics England/Genomic Medicine Centres (GE/GMC) diagnostic pipeline, 13 unrelated families were solved (13/78, 17%). Further interrogation using an expanded gene panel yielded a molecular diagnosis in 7 more unrelated families (7/78, 9%). This analysis effectively raises the total number of solved CG families in the GE100KGP to 26% (20/78 families). Twenty-five percent (5/20) of the solved families had primary congenital glaucoma (PCG), while 75% (15/20) had secondary CG; 53% of this group had non-acquired ocular anomalies (including iris hypoplasia, megalocornea, ectopia pupillae, retinal dystrophy, and refractive errors) and 47% had non-acquired systemic diseases such as cardiac abnormalities, hearing impairment, and developmental delay. CYP1B1 was the most frequently implicated gene, accounting for 55% (11/20) of the solved families. We identified two novel likely pathogenic variants in the TEK gene, in addition to one novel pathogenic copy number variant (CNV) in FOXC1. Variants that passed undetected in the GE100KGP diagnostic pipeline were likely due to limitations of the tiering process, the use of smaller gene panels during analysis, and the prioritisation of coding SNVs and indels over larger structural variants, CNVs, and non-coding variants.
摘要：
儿童青光眼（CG）包括一组异质性的遗传性眼病，约占全球儿童失明的5％。了解分子病因是提高诊断的关键，预后和解锁优化临床管理的潜力。在这项研究中,我们调查了来自78个不同种族背景的无关家庭的86例CG病例，招募到基因组英格兰100,000基因组计划（GE100KGP）罕见疾病队列，以提高基因诊断产量。使用基因组英格兰/基因组医学中心（GE/GMC）诊断管道，解决了13个无关家庭（13/78，17％）。使用扩展的基因小组进行进一步的询问在另外7个无关的家族中产生了分子诊断（7/78，9％）。该分析有效地将GE100KGP中解决的CG家族的总数提高到26%(20/78家族)。25%（5/20）的解决家庭患有原发性先天性青光眼（PCG），而75％（15/20）患有继发性CG；该组中有53％患有非获得性眼部异常（包括虹膜发育不全，巨角膜,伞状异位,视网膜营养不良,和屈光不正）和47％的人患有非获得性全身性疾病，例如心脏异常，听力障碍,和发育迟缓。CYP1B1是最常见的基因，占解决家庭的55%(11/20)。我们在TEK基因中发现了两种新的可能的致病变异，除了FOXC1中的一个新的致病性拷贝数变异体(CNV)。在GE100KGP诊断管道中未检测到的变体可能是由于分层过程的限制，在分析过程中使用较小的基因面板，以及编码SNV和indel相对于较大结构变体的优先级，CNVs,和非编码变体。
