Leber congenital amaurosis (LCA), primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy (IRD) responsible for congenital blindness. The presence of phenotypic heterogeneity makes the diagnosis of LCA challenging, especially in the absence of pronounced disease pathognomonic, yet it can be well comprehended by employing molecular diagnosis. Therefore, the present study aimed to reveal the causative mutations in ten LCA patients with variable phenotypes using clinical exome sequencing (CES). CES was performed in ten unrelated LCA patients. Ophthalmic information and family history of all patients were obtained to make a meaningful interpretation. The clinical exome data was analyzed and prioritized using a bioinformatics pipeline to identify mutations, which was further validated by Sanger sequencing. Segregation analysis was also performed on available family members. CES led to the identification of causative mutations in nine LCA patients. Seven patients harbored a mutation in six LCA candidate genes, including RPE65, LCA5 (n = 2), CRX, PRPH2, CEP290, and ALMS1, while two patients possess a mutation in IFT80 and RP1, known to cause other diseases. Three novel mutations in LCA5 (c.1823del), CRX (c.848del) and CEP290 (c.2483G > T) were identified. The current study reports for the first time, a mutation in PRPH2, CEP290, and ALMS1 from the Indian population. Additionally, we observed a novel association of LCA phenotype with IFT80 known to cause Jeune syndrome. Based on the genetic finding, the patient AS09, who harbored a mutation in the RP1 gene, was re-diagnosed with early-onset retinitis pigmentosa. In conclusion, the results underline the importance of CES in clinically diagnosed LCA patients with variable phenotypes. The correlation between mutations in candidate genes and clinical phenotypes, helps to refine the clinical diagnosis. However, molecular evaluation with a larger cohort of LCA patients is needed for better understanding of the mutational spectrum in southern India.

中文翻译：

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临床外显子组测序有助于了解印度南部Leber先天性黑名单病患者的遗传异质性

莱伯先天性黑蒙症（LCA）主要特征在于视网膜变性，是导致先天性失明的遗传性视网膜营养不良（IRD）的最严重形式。表型异质性的存在使LCA的诊断具有挑战性，尤其是在没有明显的疾病病原学的情况下，但是通过分子诊断可以很好地理解它。因此，本研究旨在通过临床外显子组测序（CES）揭示十名具有可变表型的LCA患者的致病突变。在十名无关的LCA患者中进行了CES。获得了所有患者的眼科信息和家族史，以做出有意义的解释。使用生物信息学管道分析临床外显子组数据并确定优先级，以鉴定突变，并通过Sanger测序进一步验证。还对可用的家庭成员进行了隔离分析。CES导致了9名LCA患者的致病突变的鉴定。七名患者在六个LCA候选基因中具有突变，包括RPE65，LCA5（n = 2），CRX，PRPH2，CEP290和ALMS1，而两名患者在IFT80和RP1中具有已知引起其他疾病的突变。在LCA5（c.1823del），CRX（c.848del）和CEP290（c.2483G> T）中鉴定出三个新突变。本研究首次报道了印度人群中PRPH2，CEP290和ALMS1的突变。此外，我们观察到LCA表型与已知引起Jeune综合征的IFT80的新型关联。根据遗传发现，对具有RP1基因突变的AS09患者进行了早期色素性视网膜炎的重新诊断。综上所述，结果强调了CES在临床诊断的具有可变表型的LCA患者中的重要性。候选基因突变与临床表型之间的相关性有助于改善临床诊断。然而，为了更好地了解印度南部的突变谱，需要对更多的LCA患者进行分子评估。