Combined genetic analyses can achieve efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome

• Published in: Acta Paediatrica Vol. 106; no. 11; pp. 1817 - 1824
• Main Authors: Ohashi, Kei, Togawa, Takao, Sugiura, Tokio, Ito, Koichi, Endo, Takeshi, Aoyama, Kohei, Negishi, Yutaka, Kudo, Toyoichiro, Ito, Reiko, Saitoh, Shinji
• Format: Journal Article
• Language: English
• Published: Norway Wiley Subscription Services, Inc 01.11.2017
• Subjects: Alagille syndrome; Alagille Syndrome - diagnosis; Alagille Syndrome - genetics; Biliary atresia; Biliary Atresia - genetics; Clonal deletion; Comparative Genomic Hybridization; Copy number; Female; Gene deletion; Genetic analysis; Genetic Testing; Humans; Insertion; Jagged-1 Protein - genetics; Jagged1 protein; Male; Microarray comparative genomic hybridisation; Multiplex ligation probe amplification; Multiplex Polymerase Chain Reaction; Mutation; Next‐generation sequencing; Biliary atresia; Next-generation sequencing; Multiplex ligation probe amplification; Microarray comparative genomic hybridisation; Alagille syndrome
• ISSN: 0803-5253; 1651-2227; 1651-2227
• DOI: 10.1111/apa.13981

Aim We evaluated combined genetic analyses with targeted next‐generation sequencing (NGS), multiplex ligation probe amplification (MLPA) of Jagged1 (JAG1) genes and microarray comparative genomic hybridisation (CGH) in subjects with Alagille syndrome, incomplete clinical features of Alagille syndrome and biliary atresia. Methods Subjects recruited from April 2013 to December 2015 underwent a targeted NGS analysis, including JAG1 and Notch homolog 2 (NOTCH2). If no mutations were detected in JAG1 or NOTCH2, or if copy number variations were suggested by the NGS analysis, we performed an MLPA analysis of JAG1. We also performed a microarray CGH analysis with whole‐exon deletion detected by the MLPA analysis. Results We analysed 30 subjects with Alagille syndrome, nine with incomplete Alagille syndrome and 17 with biliary atresia and detected pathogenic mutations in JAG1 or NOTCH2 in 24/30 subjects with Alagille syndrome and in 4/9 subjects with incomplete Alagille syndrome. No pathogenic mutations were detected in subjects with biliary atresia. The frequency of JAG1 mutations was as follows: single nucleotide variants (51.9%), small insertion or deletion (29.6%) and gross deletion (18.5%). Conclusion Combined genetic analyses achieved efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome.