Worapoj Jinda1, Todd D Taylor2, Yutaka Suzuki3, Wanna Thongnoppakhun4, Chanin Limwongse5, Patcharee Lertrit1, Adisak Trinavarat6, La-Ongsri Atchaneeyasakul7. 1. Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 2. Laboratory for Integrated Bioinformatics, Core for Precise Measuring and Modeling, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan. 3. Department of Medical Genome Sciences, The University of Tokyo, Kashiwa, Chiba, Japan. 4. Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 5. Division of Molecular Genetics, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 5Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 6. Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 7. Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand 6Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Abstract
Purpose: Our goal was to describe the clinical and molecular genetic findings in Thai patients with Leber congenital amaurosis (LCA). Methods: Whole exome sequencing (WES) was performed in eight unrelated patients. All genes responsible for inherited retinal diseases (IRDs) based on RetNet were selected for analysis. Potentially causative variants were filtered through a bioinformatics pipeline and validated using Sanger sequencing. Segregation analysis of the causative genes was performed in family members when available. Results: Eleven deleterious variants, six nonsense and five missense, were identified in seven genes: four LCA-associated genes (CEP290, IQCB1, NMNAT1, and RPGRIP1), one gene responsible for syndromic LCA (ALMS1), and two IRDs-related genes (CTNNA1 and CYP4V2). Clinical reassessment supported the diagnosis of syndromic LCA in those patients harboring potentially pathogenic variants in the ALMS1. Interestingly, two causative genes, CTNNA1 and CYP4V2, previously reported to cause butterfly-shaped pigment dystrophy (BSPD) and Bietti's crystalline dystrophy (BCD), respectively, were detected in two other patients. These two patients developed rapid and severe visual loss in contrast to BSPD and BCD patients in previous studies. The results of this study demonstrate that causative variants identified in the CTNNA1 and CYP4V2 genes are also associated with LCA. Conclusions: This is the first report describing the molecular genetics and clinical manifestations of Thai patients with LCA. The present study expands the spectrum of LCA-associated genes, which is a benefit for molecular diagnosis. The identification of mutations in the CTNNA1 and CYP4V2 genes requires further elucidation in larger cohorts with LCA.
Purpose: Our goal was to describe the clinical and molecular genetic findings in Thai patients with Leber congenital amaurosis (LCA). Methods: Whole exome sequencing (WES) was performed in eight unrelated patients. All genes responsible for inherited retinal diseases (IRDs) based on RetNet were selected for analysis. Potentially causative variants were filtered through a bioinformatics pipeline and validated using Sanger sequencing. Segregation analysis of the causative genes was performed in family members when available. Results: Eleven deleterious variants, six nonsense and five missense, were identified in seven genes: four LCA-associated genes (CEP290, IQCB1, NMNAT1, and RPGRIP1), one gene responsible for syndromic LCA (ALMS1), and two IRDs-related genes (CTNNA1 and CYP4V2). Clinical reassessment supported the diagnosis of syndromic LCA in those patients harboring potentially pathogenic variants in the ALMS1. Interestingly, two causative genes, CTNNA1 and CYP4V2, previously reported to cause butterfly-shaped pigment dystrophy (BSPD) and Bietti's crystalline dystrophy (BCD), respectively, were detected in two other patients. These two patients developed rapid and severe visual loss in contrast to BSPD and BCDpatients in previous studies. The results of this study demonstrate that causative variants identified in the CTNNA1 and CYP4V2 genes are also associated with LCA. Conclusions: This is the first report describing the molecular genetics and clinical manifestations of Thai patients with LCA. The present study expands the spectrum of LCA-associated genes, which is a benefit for molecular diagnosis. The identification of mutations in the CTNNA1 and CYP4V2 genes requires further elucidation in larger cohorts with LCA.
Authors: Imen Habibi; Yosra Falfoul; Ahmed Turki; Asma Hassairi; Khaled El Matri; Ahmed Chebil; Daniel F Schorderet; Leila El Matri Journal: Sci Rep Date: 2020-07-08 Impact factor: 4.379