Abstract
BackgroundLeber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families.MethodsSingle Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families.ResultsThe molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group.ConclusionsThis study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.
Highlights
Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies
We focused on a group of 22 families (28 patients) with LCA diagnosis fully confirmed by the results of molecular analysis based on Single Nucleotide Polymorphism (SNP) microarray and NGSLCA panel
In one patient (3–7), a clinical examination performed a few years after establishing the LCA molecular diagnosis revealed some features characteristic of Joubert syndrome: chronic renal failure and psychomotor development delayed
Summary
Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of inherited blindness in children. LCA is the most severe form of all inherited retinal dystrophies (IRD) and accounts for about 5% of all IRDs. The disease typically becomes evident in the first year of life, and it is estimated that about 20% of children with visual impairment in specialized schools are affected by LCA [1]. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 families living in Poland
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