The summaries are free for public
use. The Chronic Liver Disease
Foundation will continue to add and
archive summaries of articles deemed
relevant to CLDF by the Board of
Trustees and its Advisors.
Abstract Details
Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results
Genet Med. 2021 Feb;23(2):323-330. doi: 10.1038/s41436-020-00989-8. Epub 2020 Oct 20.
Ramakrishnan Rajagopalan12, Melissa A Gilbert1, Deborah A McEldrew1, James A Nassur1, Kathleen M Loomes3, David A Piccoli3, Ian D Krantz45, Laura K Conlin1, Nancy B Spinner67
Author information
1Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
2School of Biomedical Engineering, Health and Sciences, Drexel University, Philadelphia, PA, USA.
3Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
4Roberts Individualized Medical Genetics Center, Division of Human Genetics at the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
5Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
6Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. spinner@email.chop.edu.
7Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. spinner@email.chop.edu.
Abstract
Purpose: Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive result by standard-of-care testing.
Methods: We performed GS on 16 pathogenic variant-negative probands and two probands with inconclusive results (of 406 ALGS probands) and analyzed the data for sequence, copy-number, and structural variants in JAG1 and NOTCH2.
Results: GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant in JAG1, and a partial NOTCH2 deletion, for an additional diagnostic yield of 0.9%. Furthermore, GS resolved two complex rearrangements, resulting in identification of a pathogenic variant in 97.5% (n = 396/406) of patients after GS.
Conclusion: GS provided an increased diagnostic yield for individuals with clinically defined ALGS who had prior negative or incomplete genetic testing by other methods. Our results show that GS can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.