Genomic Testing in Adults With Undiagnosed Rare Conditions: Improvement of Diagnosis Using Clinical Exome Sequencing as a First‐Tier Approach

Adult patients with undiagnosed genetic disorders suffer most from diagnostic delay and seldom appear in cohort studies investigating the diagnostic yield in medical genetic clinical practice. Here we present the results of the diagnostic activity performed in a referral center on 654 consecutive, unselected adult subjects presenting with molecularly unsolved conditions. More than 50% of the referred individuals were affected by syndromic or isolated intellectual disability. Different molecular approaches, including clinical/whole exome sequencing (CES/WES), chromosomal microarray analysis (CMA), and/or targeted gene or gene panel sequencing were used to analyze patients' DNA. Definitive diagnosis was obtained in over 30% of individuals. The most sensitive methodology was CES/WES, which allowed us to reach a diagnosis in over 50% of the 162 solved cases. Despite the great variety of clinical presentations, our results represent a reliable picture of the "real world" daily routine in an outpatient medical genetics clinic dedicated to diagnostic activity, and contribute to better understand the great value of a definitive molecular diagnosis in adults, either for the affected individuals and their families. This retrospective analysis demonstrates the importance of adopting a genomic-first approach within the diagnostic process for adults affected with unsolved rare conditions.

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Publication Details

Journal
Clinical Genetics
Published
2025-02-01
DOI
https://doi.org/10.1111/cge.14715
Citations
3
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
5.45

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article

Genomic Testing in Adults With Undiagnosed Rare Conditions: Improvement of Diagnosis Using Clinical Exome Sequencing as a First‐Tier Approach

Cecilia Mancini, Massimiliano Chetta, Marcello Niceta, Serena Torre et al.
3 citations
Clinical Genetics
Genomics and Rare Diseases
5.45
article

Genomic Testing in Adults With Undiagnosed Rare Conditions: Improvement of Diagnosis Using Clinical Exome Sequencing as a First‐Tier Approach

Cecilia Mancini, Massimiliano Chetta, Marcello Niceta, Serena Torre, Alessandra Tessa, Alessandro Tessitore, Elvira Sannino, Antonio Novelli, Ilaria Maggio, Achille Iolascon, Adele Dattola, Paola D′Ambrosio, Alessandro Bruselles, Luigi Chiriatti, Tiziana Fioretti, Carmelo Piscopo, Marco Tartaglia, Maria Rivieccio, Antonella Telese, Valerio De Stefano, Marcella D’Antonio, Matteo Della Monica, Maria Oro, Mario Cioce, Francesca Clementina Radio, Corrado Mammì, Manuela Priolo, Filippo Maria Santorelli, Marco Rambaldi, Viviana Cordeddu, Marina Tarsitano, Gabriella Esposito, Roberta Petillo, Michael Parisi
article en
3 citations

Abstract

Adult patients with undiagnosed genetic disorders suffer most from diagnostic delay and seldom appear in cohort studies investigating the diagnostic yield in medical genetic clinical practice. Here we present the results of the diagnostic activity performed in a referral center on 654 consecutive, unselected adult subjects presenting with molecularly unsolved conditions. More than 50% of the referred individuals were affected by syndromic or isolated intellectual disability. Different molecular approaches, including clinical/whole exome sequencing (CES/WES), chromosomal microarray analysis (CMA), and/or targeted gene or gene panel sequencing were used to analyze patients' DNA. Definitive diagnosis was obtained in over 30% of individuals. The most sensitive methodology was CES/WES, which allowed us to reach a diagnosis in over 50% of the 162 solved cases. Despite the great variety of clinical presentations, our results represent a reliable picture of the "real world" daily routine in an outpatient medical genetics clinic dedicated to diagnostic activity, and contribute to better understand the great value of a definitive molecular diagnosis in adults, either for the affected individuals and their families. This retrospective analysis demonstrates the importance of adopting a genomic-first approach within the diagnostic process for adults affected with unsolved rare conditions.

Clinical GeneticsVol. 108(2)
University of Campania "Luigi Vanvitelli" (IT), Istituto Superiore di Sanità (IT), Ospedale Maggiore (IT), Ospedale Antonio Cardarelli (IT), Bambino Gesù Children's Hospital (IT), Fondazione Stella Maris (IT), CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Naples Federico II (IT)
Ministero della Salute, Fondazione Bambino Gesù
Openalex Percentile: Top 6%
Genomics and Rare Diseases
5.45
DOIOpen Access PDFOpenAlex
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