Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results

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 inJAG1andNOTCH2. Results GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant inJAG1, and a partialNOTCH2deletion, 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.

Automated summary

This study aimed to demonstrate the utility of genome sequencing (GS) in diagnosing patients with Alagille syndrome and found four novel pathogenic alterations, increasing the diagnostic yield. GS was able to resolve complex rearrangements, resulting in identification of a pathogenic variant in 97.5% of patients after GS.