Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy.
Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli Federico II, 80131 Naples, Italy.
Genes (Basel). 2024 Aug 6;15(8):1034. doi: 10.3390/genes15081034.
Alagille syndrome (ALGS) is a rare autosomal dominant genetic disease caused by pathogenic variants in two genes: Jagged Canonical Notch Ligand 1 () and Notch Receptor 2 (). It is characterized by phenotypic variability and incomplete penetrance with multiorgan clinical signs.
Using Next Generation Sequencing (NGS), we analyzed a panel of liver-disease-related genes in a population of 230 patients with cholestasis and hepatopathies. For the rare variants, bioinformatics predictions and pathogenicity classification were performed.
We identified eleven rare variants in 10 patients, two variants being present in the same patient. Ten variants had never been described before in the literature. It was possible to classify only two null variants as pathogenic, whereas the most of variants were missense (8 out of 11) and were classified as uncertain significance variants (USVs). Among patients with ALGS suspicion, two carried null variants, two carried variants predicted to be pathogenic by bioinformatics, one carried a synonymous variant and variants in glycosylation-related genes, and two carried variants predicted as benign in the PEST domain.
Our results increased the knowledge about variants and the related phenotype, allowing us to improve the genetic diagnosis of ALGS.
Alagille 综合征（ALGS）是一种罕见的常染色体显性遗传疾病，由两个基因的致病性变异引起：Jagged Canonical Notch Ligand 1（JAG1）和 Notch Receptor 2（NOTCH2）。它的特点是表型变异性和不完全外显率，具有多器官临床体征。
我们使用下一代测序（NGS）分析了 230 名胆汁淤积和肝病患者的一组肝脏疾病相关基因。对于罕见的变异，进行了生物信息学预测和致病性分类。
我们在 10 名患者中发现了 11 个罕见的变体，其中两个变体存在于同一名患者中。这 10 个变体以前从未在文献中描述过。只有两个无效变异被归类为致病性，而大多数变异是错义（11 个中的 8 个），被归类为意义不明的变异（USVs）。在有 ALGS 可疑症状的患者中，两名患者携带无效变异，两名患者携带生物信息学预测为致病性的变异，一名患者携带同义变异和糖基化相关基因的变异，两名患者携带 PEST 结构域预测为良性的变异。
我们的研究结果增加了对 变异体及其相关表型的认识，使我们能够提高 ALGS 的遗传诊断。
