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Molecular and clinical characterization of Thai patients with achromatopsia: identification of three novel disease-associated variants in the CNGA3 and CNGB3 genes

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Abstract

Purpose

Achromatopsia (ACHM) is an autosomal recessive cone disorder characterized by pendular nystagmus, photophobia, reduced visual acuity, and partial or total absence of color vision. Mutations in six genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6) have been reported in ACHM. There is no information on these disease-associated genes in Thai population. This study aimed to investigate the molecular and clinical characteristics in Thai patients with ACHM.

Methods

Seven unrelated Thai patients with ACHM were recruited. Detailed ophthalmologic examination was performed. Polymerase chain reaction (PCR)-coupled single-strand conformation polymorphism (SSCP) screening followed by Sanger sequencing was used to identify sequence variants in all exons and splice junctions of three genes (CNGA3, CNGB3, and GNAT2). The pathogenicity of the detected variants was interpreted. Segregation analysis was performed to determine variant sharing in available family members.

Results

Four patients displayed different SSCP migration patterns. Sequence analysis revealed a reported pathogenic and a novel disease-associated variant in the CNGA3 gene. For the CNGB3 gene, we found two novel disease-associated variants and a reported variant of uncertain significance (VUS). Segregation analysis confirmed that the variants identified in each patient were present in the heterozygous state in their corresponding family members, which was consistent with an autosomal recessive mode of inheritance.

Conclusions

This study demonstrated the first molecular and clinical characterization of ACHM in Thai patients. The identification of disease-associated genes in a specific population leads to a personalized gene therapy benefiting those affected patients.

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Acknowledgements

The authors would like to thank the patients, their families and the normal volunteers who participated in the study.

Funding

This work was supported by the Siriraj Foundation (L-OA); the Chalermphrakiat Grant, Faculty of Medicine Siriraj Hospital, Mahidol University (L-OA, WT, CL).

Author information

Authors and Affiliations

  1. Division of Medical Genetics Research and Laboratory, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Worapoj Jinda, Wanna Thongnoppakhun & Chanin Limwongse

  2. Clinical Molecular Pathology Laboratory, Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Aekkachai Tuekprakhon

  3. Division of Medical Genetics, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Chanin Limwongse

  4. Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand

    Adisak Trinavarat & La-ongsri Atchaneeyasakul

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  1. Worapoj Jinda
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  2. Aekkachai Tuekprakhon
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  3. Wanna Thongnoppakhun
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  5. Adisak Trinavarat
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  6. La-ongsri Atchaneeyasakul
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Correspondence to La-ongsri Atchaneeyasakul.

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Fig. S1

Multiple protein sequence alignment of the CNGA3 and CNGB3 proteins across different species. Arrows indicate the variants sites located in highly conserved region of the CNGA3 and CNGB3 protein. “*”—single, fully conserved residue, “:”—conservation of strong groups, “.”—conservation of weak groups, and “_”—no consensus (TIFF 3795 kb)

Table S1

List of oligonucleotides used as PCR primers for SSCP analysis and product lengths. F: Forward primer. R: Reverse primer (DOCX 24 kb)

Table S2

In silico pathogenicity prediction of variants (DOCX 13 kb)

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Jinda, W., Tuekprakhon, A., Thongnoppakhun, W. et al. Molecular and clinical characterization of Thai patients with achromatopsia: identification of three novel disease-associated variants in the CNGA3 and CNGB3 genes. Int Ophthalmol 41, 121–134 (2021). https://doi.org/10.1007/s10792-020-01559-2

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