目的分析中国汉族全色盲一家系的临床特征和致病基因变异。
方法采用家系调查研究方法，收集2010年7月至2019年7月于北京协和医院眼科就诊的中国汉族全色盲一家系，纳入该家系2代5名成员，包括2例患者和3名表型正常者。询问病史并进行详细眼科检查，包括视力、色觉、彩色眼底照相、眼底自发荧光(FAF)、光相干断层扫描(OCT)、视野及视网膜电图(ERG)检查。采集2例患者及家系成员外周血并提取DNA。利用全外显子测序(WES)技术筛选致病基因变异，进行Sanger验证及家系共分离分析。通过1000 Genomes、人类基因突变数据库(HGMD)、ExAC、ClinVar以及OMIM等数据库对变异位点进行注释，判断是否为单核苷酸多态性或已报道变异；根据美国医学遗传学和基因组学(ACMG)遗传变异分类标准与指南进行致病性评估。
结果先证者父母近亲结婚，家系遗传特点符合常染色体隐性遗传。2例患者均为男性，均自幼双眼视力低下伴有畏光和色觉障碍。眼底表现为黄斑中心凹处反光不明显。FAF显示黄斑中心凹处弱荧光。OCT显示未见明显黄斑中心凹结构，且相应区域椭圆体带和交接带缺失。视野检查显示中心暗点伴或不伴周边视野缺损。ERG显示暗适应0.01、3.0及10.0反应波形大致正常；振荡电位振幅下降；明适应3.0及30 Hz闪烁光反应未记录到波形。随诊9年，患者的临床表现显示疾病未见明显进展。测序结果显示2例患者均携带纯合 ATF6基因新发致病变异c.947insA(p.Asn316Lysfs*46)，先证者母亲携带杂合变异，未患病的胞兄弟未携带变异，符合家系共分离。ACMG遗传变异分类标准与指南评级为致病性变异。
结论 ATF6基因c.947insA(p.Asn316Lysfs*46)为该全色盲家系的致病基因变异位点，该变异位点为首次报道。
ObjectiveTo identify the clinical characteristics and pathogenic gene of a Chinese Han family with achromatopsia (ACHM).
MethodsThe method of pedigree investigation was adopted.A Chinese Han ACHM family was recruited in Peking Union Medical College Hospital form July 2010 to July 2019, including 5 members of 2 generations.There were 2 patients and 3 phenotypically normal individuals.The medical history was collected and comprehensive ophthalmic examinations were performed, including visual acuity, colour vision, color fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT), visual field and electroretinogram (ERG).Genomic DNA was extracted from peripheral blood sample from the patients and family members.Pathogenic variant was screened by whole exome sequencing (WES) and verified by Sanger sequencing and co-segregation analysis.The variant was annotated with the 1000 Genomes, Human Gene Mutation Database (HGMD), ExAC, ClinVar and OMIM databases to detect the single nucleotide polymorphism and whether it had been reported previously.The pathogenicity of the variant was evaluated according to the standards and guidelines of the American College of Medical Genetics and Genomics (ACMG).This study adhered to the Declaration of Helsinki.The study protocol was approved by the Institutional Review Board of Peking Union Medical College Hospital (No.JS-2059).Written informed consent was obtained from the guardians of juvenile patients.
ResultsThere was consanguinity between the proband's parents and this family was consistent with autosomal recessive inheritance.Both male patients presented the reduction of visual acuity accompanied with photophobia and color blindness since childhood.Barely visible foveal light reflex in fundus images, hypofluorescence of foveal areas in FAF images, foveal defect with disruption of ellipsoid zone and interdigitation zone in OCT images were found in both patients.Central scotoma with or without peripheral visual field defects was detected.Generally normal scotopic 0.01, 3.0 and 10.0 responses, decreased oscillatory potentials amplitudes, no photopic 3.0 and 30 Hz flicker responses were observed.No sign of progression was found during the 9-year follow-up.It was confirmed that both patients carried a novel homozygous disease-causing variant c. 947insA (p.Asn316Lysfs*46) in ATF6 gene.Their mother had the heterozygous variant.The unaffected brother did not carry the variant.This family was consistent with co-segregation.This variant was labeled as pathogenic according to the ACMG standards and guidelines.
ConclusionsA novel variant c.947insA (p.Asn316Lysfs*46) in ATF6 gene is the pathogenic variant of this achromatopsia family.This is the first time that this variant has been reported.
朱田,李蕙,卫星,等. 中国 ATF6基因相关全色盲一家系分子遗传学和临床特征分析 [J]. 中华实验眼科杂志,2022,40(10)：948-954.
DOI:10.3760/cma.j.cn115989-20210909-00506版权归中华医学会所有。
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朱田：直接参与选题、设计试验、实施研究、采集数据、分析解释数据和起草文章；李蕙、卫星、吴世靖、孙子系：采集数据、解释数据；睢瑞芳：直接参与选题、酝酿和设计试验、采集数据、分析/解释数据、对文章知识性内容的审阅和智力性内容的修改及定稿
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