Fernández-Suárez Elena, González-Del Pozo María, García-Núñez Alejandro, Méndez-Vidal Cristina, Martín-Sánchez Marta, Mejías-Carrasco José Manuel, Ramos-Jiménez Manuel, Morillo-Sánchez María José, Rodríguez-de la Rúa Enrique, Borrego Salud, Antiñolo Guillermo
Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/Spanish National Research Council (CSIC)/University of Seville, Seville, Spain.
Center for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain.
Front Cell Dev Biol. 2023 Jul 21;11:1197744. doi: 10.3389/fcell.2023.1197744. eCollection 2023.
Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of disorders that often severely impair vision. Some patients manifest poor central vision as the first symptom due to cone-dysfunction, which is consistent with cone dystrophy (COD), Stargardt disease (STGD), or macular dystrophy (MD) among others. Here, we aimed to identify the genetic cause of autosomal dominant COD in one family. WGS was performed in 3 affected and 1 unaffected individual using the TruSeq Nano DNA library kit and the NovaSeq 6,000 platform (Illumina). Data analysis identified a novel spliceogenic variant (c.283 + 1G>A) in the thyroid hormone receptor beta gene () as the candidate disease-associated variant. Further genetic analysis revealed the presence of the same heterozygous variant segregating in two additional unrelated dominant pedigrees including 9 affected individuals with a diagnosis of COD (1), STGD (4), MD (3) and unclear phenotype (1). has been previously reported as a causal gene for autosomal dominant and recessive thyroid hormone resistance syndrome beta (RTHβ); however, none of the IRD patients exhibited RTHβ. Genotype-phenotype correlations showed that RTHβ can be caused by both truncating and missense variants, which are mainly located at the 3' (C-terminal/ligand-binding) region, which is common to both isoforms (TRβ1 and TRβ2). In contrast, the c.283 + 1G>A variant is predicted to disrupt a splice site in the 5'-region of the gene that encodes the N-terminal domain of the TRβ1 isoform protein, leaving the TRβ2 isoform intact, which would explain the phenotypic variability observed between RTHβ and IRD patients. Interestingly, although monochromacy or cone response alterations have already been described in a few RTHβ patients, herein we report the first genetic association between a pathogenic variant in and non-syndromic IRDs. We thereby expand the phenotype of pathogenic variants including COD, STGD, or MD as the main clinical manifestation, which also reflects the extraordinary complexity of retinal functions mediated by the different isoforms.
遗传性视网膜营养不良（IRDs）是一组临床和遗传异质性疾病，常严重损害视力。一些患者由于视锥细胞功能障碍，以中心视力差作为首发症状，这与视锥细胞营养不良（COD）、斯塔加特病（STGD）或黄斑营养不良（MD）等疾病相符。在此，我们旨在确定一个家族中常染色体显性遗传性COD的遗传病因。使用TruSeq Nano DNA文库试剂盒和NovaSeq 6000平台（Illumina）对3名患病个体和1名未患病个体进行了全基因组测序（WGS）。数据分析确定甲状腺激素受体β基因（）中的一个新的剪接变异（c.283 + 1G>A）为候选疾病相关变异。进一步的遗传分析显示，另外两个无关的显性家系中也存在相同的杂合变异，这两个家系包括9名被诊断为COD（1例）、STGD（4例）、MD（3例）和表型不明（1例）的患病个体。此前已报道该基因是常染色体显性和隐性甲状腺激素抵抗综合征β型（RTHβ）的致病基因；然而，没有一名IRD患者表现出RTHβ。基因型-表型相关性表明，RTHβ可由截短变异和错义变异引起，这些变异主要位于两种异构体（TRβ1和TRβ2）共有的3'（C端/配体结合）区域。相比之下，c.283 + 1G>A变异预计会破坏编码TRβ1异构体蛋白N端结构域的基因5'区域的一个剪接位点，而TRβ2异构体保持完整，这可以解释RTHβ患者和IRD患者之间观察到的表型变异性。有趣的是，尽管在少数RTHβ患者中已经描述了全色盲或视锥细胞反应改变，但在此我们报道了该基因的一个致病变异与非综合征性IRD之间的首次遗传关联。我们从而扩展了该基因致病变异的表型，包括以COD、STGD或MD为主要临床表现型，这也反映了由不同异构体介导的视网膜功能的异常复杂性。
