PDF(Pubmed)
Abstract：
Inherited retinal diseases (IRDs) represent a spectrum of clinically and genetically heterogeneous disorders. Our study describes an IRD patient carrying ABCA4 and USH2A pathogenic biallelic mutations as a result of paternal uniparental disomy (UPD) in chromosome 1. The proband is a 9-year-old girl born from non-consanguineous parents. Both parents were asymptomatic and denied family history of ocular disease. Clinical history and ophthalmologic examination of the proband were consistent with Stargardt disease. Whispered voice testing disclosed moderate hearing loss. Next-generation sequencing and Sanger sequencing identified pathogenic variants in ABCA4 (c.4926C>G and c.5044_5058del) and USH2A (c.2276G>T). All variants were present homozygously in DNA from the proband and heterozygously in DNA from the father. No variants were found in maternal DNA. Further analysis of single nucleotide polymorphisms confirmed paternal UPD of chromosome 1. This is the first known patient with confirmed UPD for two recessively mutated IRD genes. Our study expands on the genetic heterogeneity of IRDs and highlights the importance of UPD as a mechanism of autosomal recessive disease in non-consanguineous parents. Moreover, a long-term follow-up is essential for the identification of retinal features that may develop as a result of USH2A-related conditions.
摘要：
遗传性视网膜疾病（IRD）代表了一系列临床和遗传异质性疾病。我们的研究描述了一名IRD患者，该患者携带ABCA4和USH2A致病性双等位基因突变，这是由于1号染色体上的父系单亲二体性（UPD）所致。先证者是一个9岁的女孩，来自非近亲父母。父母双方均无症状，否认眼部疾病家族史。先证者的临床病史和眼科检查与Stargardt病一致。低语语音测试显示中度听力损失。下一代测序和Sanger测序鉴定了ABCA4(c.4926C>G和c.5044_5058del)和USH2A(c.2276G>T)中的致病变体。所有变体均纯合存在于先证者的DNA中，杂合存在于父亲的DNA中。在母体DNA中未发现变异。单核苷酸多态性的进一步分析证实了1号染色体的父系UPD。这是第一个已知的患者，证实了UPD的两个间接突变的IRD基因。我们的研究扩展了IRD的遗传异质性，并强调了UPD作为非近亲父母常染色体隐性疾病机制的重要性。此外，长期随访对于识别可能由USH2A相关疾病引起的视网膜特征至关重要.
