Abstract：
Retinitis pigmentosa (RP) is the most common type of inherited retinopathy. At least 69 genes for RP have been identified. A significant proportion of RP, however, remains genetically unsolved. In this study, the genetic basis of a Chinese consanguineous family with presumed autosomal recessive retinitis pigmentosa (arRP) was investigated.
Overall ophthalmic examinations, including funduscopy, decimal best-corrected visual acuity, axial length and electroretinography (ERG) were performed for the family. Genomic DNA from peripheral blood of the proband was subjected to whole exome sequencing. In silico predictions, structural modelling, and minigene assays were conducted to evaluate the pathogenicity of the variant.
A novel homozygous variant (NM_003320.4: c.1379A > G) in the TUB gene was identified as a candidate pathogenic variant in this parental consanguineous pedigree. This variant co-segregated with the disease in this pedigree and was absent in 118 ethnically matched healthy controls. It\'s an extremely rare variant that is neither deposited in population databases (1000 Genomes, ExAC, GnomAD, or Exome Variant Server) nor reported in the literature. Phylogenetic analysis indicated that the Asn residue at codon 460 of TUB is highly conserved across diverse species from tropicalis to humans. It was also completely conserved among the TUB, TULP1, TULP2, and TULP3 family proteins. Multiple bioinformatic algorithms predicted that this variant was deleterious.
A novel missense variant in TUB was identified, which was probably the pathogenic basis for arRP in this consanguineous family. This is the first report of a homozygous missense variant in TUB for RP.
Overall ophthalmic examinations, including funduscopy, decimal best-corrected visual acuity, axial length and electroretinography (ERG) were performed for the family. Genomic DNA from peripheral blood of the proband was subjected to whole exome sequencing. In silico predictions, structural modelling, and minigene assays were conducted to evaluate the pathogenicity of the variant.
A novel homozygous variant (NM_003320.4: c.1379A > G) in the TUB gene was identified as a candidate pathogenic variant in this parental consanguineous pedigree. This variant co-segregated with the disease in this pedigree and was absent in 118 ethnically matched healthy controls. It\'s an extremely rare variant that is neither deposited in population databases (1000 Genomes, ExAC, GnomAD, or Exome Variant Server) nor reported in the literature. Phylogenetic analysis indicated that the Asn residue at codon 460 of TUB is highly conserved across diverse species from tropicalis to humans. It was also completely conserved among the TUB, TULP1, TULP2, and TULP3 family proteins. Multiple bioinformatic algorithms predicted that this variant was deleterious.
A novel missense variant in TUB was identified, which was probably the pathogenic basis for arRP in this consanguineous family. This is the first report of a homozygous missense variant in TUB for RP.
摘要：
背景：色素性视网膜炎（RP）是最常见的遗传性视网膜病变类型。已经鉴定了至少69个RP基因。相当比例的RP，然而,基因上仍未解决。在这项研究中,研究了一个推测常染色体隐性遗传性视网膜色素变性（arRP）的中国近亲家庭的遗传基础。
方法：总体眼科检查，包括Funduscopy，十进制最佳矫正视力，对该家族进行轴向长度和视网膜电图(ERG)检查.对来自先证者的外周血的基因组DNA进行全外显子组测序。在硅预测中，结构建模，和小基因测定进行评估，以评估该变体的致病性。
结果:TUB基因中的一种新的纯合变体(NM_003320.4:c.1379A>G)被鉴定为该亲本近亲谱系中的候选致病变体。在该谱系中，该变体与疾病共分离，在118个种族匹配的健康对照中不存在。这是一种极其罕见的变体，既不存在于人口数据库中(1000个基因组，ExAC,GnomAD,或外显子组变异服务器)也没有在文献中报道。系统发育分析表明，TUB的密码子460处的Asn残基在从热带到人类的各种物种中高度保守。它在TUB之间也完全保存了下来，TULP1、TULP2和TULP3家族蛋白。多种生物信息学算法预测该变体是有害的。
结论：在TUB中发现了一个新的错义变体，这可能是该近亲家族中arRP的致病基础。这是RP在TUB中纯合错义变体的首次报道。
方法：总体眼科检查，包括Funduscopy，十进制最佳矫正视力，对该家族进行轴向长度和视网膜电图(ERG)检查.对来自先证者的外周血的基因组DNA进行全外显子组测序。在硅预测中，结构建模，和小基因测定进行评估，以评估该变体的致病性。
结果:TUB基因中的一种新的纯合变体(NM_003320.4:c.1379A>G)被鉴定为该亲本近亲谱系中的候选致病变体。在该谱系中，该变体与疾病共分离，在118个种族匹配的健康对照中不存在。这是一种极其罕见的变体，既不存在于人口数据库中(1000个基因组，ExAC,GnomAD,或外显子组变异服务器)也没有在文献中报道。系统发育分析表明，TUB的密码子460处的Asn残基在从热带到人类的各种物种中高度保守。它在TUB之间也完全保存了下来，TULP1、TULP2和TULP3家族蛋白。多种生物信息学算法预测该变体是有害的。
结论：在TUB中发现了一个新的错义变体，这可能是该近亲家族中arRP的致病基础。这是RP在TUB中纯合错义变体的首次报道。
