Department of Experimental Medicine, Laboratory of Biochemistry, University of Perugia, Perugia, Italy.
Department of Biology, Faculty of Natural Sciences, University of Ss. Cyril and Methodius, Trnava, Slovakia.
Mol Genet Genomic Med. 2021 Apr;9(4):e1630. doi: 10.1002/mgg3.1630. Epub 2021 Mar 16.
The rapid spread of genome-wide next-generation sequencing in the molecular diagnosis of rare genetic disorders has produced increasing evidence of multilocus genomic variations in cases with a previously well-characterized molecular diagnosis. Here, we describe two patients with a rare combination of skeletal abnormalities and retinal dystrophy caused by variants in the SLC26A2 and ABCA4 genes, respectively, in a family with parental consanguinity.
Next-generation sequencing and Sanger sequencing were performed to obtain a molecular diagnosis for the retinal and skeletal phenotypes, respectively.
Genetic testing revealed that the sisters were homozygous for the p.(Cys653Ser) variant in SLC26A2 and heterozygous for the missense p.(Pro68Leu) and splice donor c.6386+2C>G variants in ABCA4. Segregation analysis confirmed the carrier status of the parents.
Despite low frequency of occurrence, the detection of multilocus genomic variations in a single disease gene-oriented approach can provide accurate diagnosis even in cases with high phenotypic complexity. A targeted sequencing approach can detect relationships between observed phenotypes and underlying genotypes, useful for clinical management.
全基因组新一代测序在罕见遗传疾病的分子诊断中的快速传播，为先前分子诊断明确的病例中多基因座基因组变异提供了越来越多的证据。在这里，我们描述了一对有亲缘关系的父母的家庭中，两名患者分别因 SLC26A2 和 ABCA4 基因的变异而出现罕见的骨骼异常和视网膜营养不良的综合病症。
分别进行下一代测序和 Sanger 测序，以获得视网膜和骨骼表型的分子诊断。
基因检测显示，这对姐妹在 SLC26A2 中为纯合子 p.(Cys653Ser)变异，在 ABCA4 中为杂合子 p.(Pro68Leu)错义变异和剪接供体 c.6386+2C>G 变异。 分离分析证实了父母的携带者状态。
尽管发生频率较低，但即使在表型高度复杂的情况下，针对单一疾病基因的多位点基因组变异的检测也可以提供准确的诊断。靶向测序方法可以检测观察到的表型与潜在基因型之间的关系，这对临床管理很有用。
