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Diagnostic application of clinical exome sequencing in Leber congenital amaurosis

 Jinu Han  ;  John Hoon Rim  ;  In Sik Hwang  ;  Jieun Kim  ;  Saeam Shin  ;  Seung-Tae Lee  ;  Jong Rak Choi 
 MOLECULAR VISION, Vol.23 : 649-659, 2017 
Journal Title
Issue Date
Adult ; Antigens, Neoplasm/genetics ; DNA Mutational Analysis ; DNA-Binding Proteins/genetics ; Exome/genetics ; Eye Proteins/genetics ; Female ; Genetic Association Studies ; Guanylate Cyclase/genetics ; High-Throughput Nucleotide Sequencing ; Homeodomain Proteins/genetics ; Humans ; Infant ; Leber Congenital Amaurosis/diagnosis ; Leber Congenital Amaurosis/genetics ; Male ; Mutation ; Neoplasm Proteins/genetics ; Nicotinamide-Nucleotide Adenylyltransferase/genetics ; Pedigree ; Proteins/genetics ; Receptors, Cell Surface/genetics ; Sequence Analysis, DNA ; Trans-Activators/genetics

Leber congenital amaurosis (LCA) is a hereditary retinal dystrophy with wide genetic heterogeneity. Next-generation sequencing (NGS) targeting multiple genes can be a good option for the diagnosis of LCA, and we tested a clinical exome panel in patients with LCA.


A total of nine unrelated Korean patients with LCA were sequenced using the Illumina TruSight One panel, which targets 4,813 clinically associated genes, followed by confirmation using Sanger sequencing. Patients' clinical information and familial study results were obtained and used for comprehensive interpretation.


In all nine patients, we identified pathogenic variations in LCA-associated genes: NMNAT1 (n=3), GUCY2D (n=2), RPGRIP1 (n=2), CRX (n=1), and CEP290 or SPATA7. Six patients had one or two mutations in accordance with inheritance patterns, all consistent with clinical phenotypes. Two patients had only one pathogenic mutation in recessive genes (NMNAT1 and RPGRIP1), and the clinical features were specific to disorders associated with those genes. Six patients were solved for genetic causes, and it remains unclear for three patients with the clinical exome panel. With subsequent targeted panel sequencing with 113 genes associated with infantile nystagmus syndrome, a likely pathogenic allele in CEP290 was detected in one patient. Interestingly, one pathogenic variant (p.Arg237Cys) in NMNAT1 was present in three patients, and it had a high allele frequency (0.24%) in the general Korean population, suggesting that NMNAT1 could be a major gene responsible for LCA in Koreans.


We confirmed that a commercial clinical exome panel can be effectively used in the diagnosis of LCA. Careful interpretation and clinical correlation could promote the successful implementation of clinical exome panels in routine diagnoses of retinal dystrophies, including LCA.
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1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Shin, Saeam(신새암) ORCID logo https://orcid.org/0000-0003-1501-3923
Lee, Seung-Tae(이승태) ORCID logo https://orcid.org/0000-0003-1047-1415
Rim, John Hoon(임정훈) ORCID logo https://orcid.org/0000-0001-6825-8479
Choi, Jong Rak(최종락) ORCID logo https://orcid.org/0000-0002-0608-2989
Han, Jinu(한진우) ORCID logo https://orcid.org/0000-0002-8607-6625
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