Diagnostic Yield of Exome and Genome Sequencing After Non-diagnostic Multi-gene Panels in Patients with Single-system Diseases

Overview

Journal Orphanet J Rare Dis

Publisher Biomed Central

Specialty General Medicine

Date 2024 May 24

PMID 38790019

Authors

Matheus V M B Wilke

Eric W Klee

Radhika Dhamija

Fernando C Fervenza

Brittany Thomas

Nelson Leung

Marie C Hogan

Megan M Hager

Kayla J Kolbert

Jennifer L Kemppainen

Elle C Loftus

Katie M Leitzen

Carolyn R Vitek

Tammy McAllister

Konstantinos N Lazaridis

Filippo Pinto E Vairo

Affiliations

Soon will be listed here.

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.

Citing Articles

Genome sequencing reveals the impact of non-canonical exon inclusions in rare genetic disease.

Pitsava G, Hawley M, Auriga L, de Dios I, Ko A, Marmolejos S medRxiv. 2025; .

PMID: 39763557 PMC: 11703292. DOI: 10.1101/2024.12.21.24318325.

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