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. 2024 May 24;19(1):216.
doi: 10.1186/s13023-024-03213-x.

Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases

Matheus V M B Wilke  1 , Eric W Klee  1   2   3 , Radhika Dhamija  2 , Fernando C Fervenza  4 , Brittany Thomas  5 , Nelson Leung  4 , Marie C Hogan  4 , Megan M Hager  6 , Kayla J Kolbert  1 , Jennifer L Kemppainen  1 , Elle C Loftus  1 , Katie M Leitzen  1 , Carolyn R Vitek  1 , Tammy McAllister  1 , Konstantinos N Lazaridis  1   7 , Filippo Pinto E Vairo  8   9
Affiliations

Diagnostic yield of exome and genome sequencing after non-diagnostic multi-gene panels in patients with single-system diseases

Matheus V M B Wilke et al. Orphanet J Rare Dis. .

Abstract

Background: Though next-generation sequencing (NGS) tests like exome sequencing (ES), genome sequencing (GS), and panels derived from exome and genome data (EGBP) are effective for rare diseases, the ideal diagnostic approach is debated. Limited research has explored reanalyzing raw ES and GS data post-negative EGBP results for diagnostics.

Results: We analyzed complete ES/GS raw sequencing data from Mayo Clinic's Program for Rare and Undiagnosed Diseases (PRaUD) patients to assess whether supplementary findings could augment diagnostic yield. ES data from 80 patients (59 adults) and GS data from 20 patients (10 adults), averaging 43 years in age, were analyzed. Most patients had renal (n=44) and auto-inflammatory (n=29) phenotypes. Ninety-six cases had negative findings and in four cases additional genetic variants were found, including a variant related to a recently described disease (RRAGD-related hypomagnesemia), a variant missed due to discordant inheritance pattern (COL4A3), a variant with high allelic frequency (NPHS2) in the general population, and a variant associated with an initially untargeted phenotype (HNF1A).

Conclusion: ES and GS show diagnostic yields comparable to EGBP for single-system diseases. However, EGBP's limitations in detecting new disease-associated genes underscore the necessity for periodic updates.

Keywords: Diagnostic yield; Exome; Gene panels; Genetic testing; Genome; Rare diseases.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Results of the re-analyses of custom clinical exome and genome-based panels data of 100 patients with single-system diseases
See this image and copyright information in PMC

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