Journal article
Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results
Genetics in medicine, v 23(2), pp 323-330
Feb 2021
PMID: 33077891
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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.
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.
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.
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Details
- Title
- Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results
- Creators
- Ramakrishnan Rajagopalan - Children's Hospital of PhiladelphiaMelissa A Gilbert - Children's Hospital of PhiladelphiaDeborah A McEldrew - Children's Hospital of PhiladelphiaJames A Nassur - Children's Hospital of PhiladelphiaKathleen M Loomes - Children's Hospital of PhiladelphiaDavid A Piccoli - Children's Hospital of PhiladelphiaIan D Krantz - Children's Hospital of PhiladelphiaLaura K Conlin - Children's Hospital of PhiladelphiaNancy B Spinner - Children's Hospital of PhiladelphiaJanell L Mensinger
- Publication Details
- Genetics in medicine, v 23(2), pp 323-330
- Publisher
- Springer Nature
- Grant note
- R01 HG009708 / NHGRI NIH HHS R01 DK081702 / NIDDK NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000579719000003
- Scopus ID
- 2-s2.0-85092693697
- Other Identifier
- 991019357630304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Genetics & Heredity