Abstract：
OBJECTIVE: 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.
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.
摘要：
目的：色盲（ACHM）是一种常染色体隐性遗传的视锥细胞疾病，其特征是摆动性眼球震颤，畏光,视力下降，部分或完全没有色觉。六个基因（CNGA3，CNGB3，GNAT2，PDE6C，PDE6H,和ATF6）已在ACHM中报告。在泰国人群中没有关于这些疾病相关基因的信息。本研究旨在探讨泰国ACHM患者的分子和临床特征。
方法：招募了7名无关的泰国ACHM患者。进行了详细的眼科检查。使用聚合酶链反应（PCR）偶联的单链构象多态性（SSCP）筛选，然后进行Sanger测序，以鉴定三个基因（CNGA3，CNGB3和GNAT2）的所有外显子和剪接接头中的序列变体。解释了检测到的变体的致病性。进行分离分析以确定可用家庭成员中的变异共享。
结果：4例患者表现出不同的SSCP迁移模式。序列分析揭示了CNGA3基因中报道的致病性和新的疾病相关变体。对于CNGB3基因，我们发现了两个新的疾病相关变异体和一个已报道的显著性不确定变异体(VUS).分离分析证实，在每个患者中鉴定出的变异体在其相应的家庭成员中以杂合状态存在，这与常染色体隐性遗传方式一致。
结论：这项研究证明了泰国患者ACHM的第一个分子和临床特征。特定人群中疾病相关基因的鉴定导致使那些受影响的患者受益的个性化基因治疗。
方法：招募了7名无关的泰国ACHM患者。进行了详细的眼科检查。使用聚合酶链反应（PCR）偶联的单链构象多态性（SSCP）筛选，然后进行Sanger测序，以鉴定三个基因（CNGA3，CNGB3和GNAT2）的所有外显子和剪接接头中的序列变体。解释了检测到的变体的致病性。进行分离分析以确定可用家庭成员中的变异共享。
结果：4例患者表现出不同的SSCP迁移模式。序列分析揭示了CNGA3基因中报道的致病性和新的疾病相关变体。对于CNGB3基因，我们发现了两个新的疾病相关变异体和一个已报道的显著性不确定变异体(VUS).分离分析证实，在每个患者中鉴定出的变异体在其相应的家庭成员中以杂合状态存在，这与常染色体隐性遗传方式一致。
结论：这项研究证明了泰国患者ACHM的第一个分子和临床特征。特定人群中疾病相关基因的鉴定导致使那些受影响的患者受益的个性化基因治疗。
