Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)
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RESEARCH
Novel gene variants in Polish patients with Leber congenital amaurosis (LCA) Anna Skorczyk‑Werner1* , Zuzanna Niedziela1,2, Marcin Stopa2 and Maciej Robert Krawczyński1,3
Abstract Background: 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. To date, 25 genes have been impli‑ cated 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. Methods: Single 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. Results: The molecular background was established in 22 families. From a total of 24 identified variants, 23 were pre‑ dicted 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 con‑ firmed 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. Conclusions: This study provides the first molecular genetic characteristics of patients with Leber congenital amau‑ rosis 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. Keywords: Leber congenital amaurosis (LCA), Novel variants, SNP-microarray for LCA genes, Targeted NGS panel for LCA genes Background 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 *Correspondence: [email protected] 1 Department of Medical Genetics, Poznan University of Medical Sciences, 8, Rokietnicka St, 60‑806 Poznan, Poland Full list of author information is available at the end of the article
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 prevalence of the disorder is estimated to be 1 in 30,000
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