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

• Published in: Clinical genetics Vol. 108; no. 2; pp. 115 - 123
• Main Authors: Petillo, Roberta, De Maggio, Ilaria, Piscopo, Carmelo, Chetta, Massimiliano, Tarsitano, Marina, Chiriatti, Luigi, Sannino, Elvira, Torre, Serena, D'Antonio, Marcella, D'Ambrosio, Paola, Rambaldi, Marco, Cioce, Maria, De Stefano, Valentina, Parisi, Maria Rita, Telese, Antonella, Oro, Maria, Rivieccio, Maria, Radio, Francesca Clementina, Mancini, Cecilia, Niceta, Marcello, Cordeddu, Viviana, Bruselles, Alessandro, Mammì, Corrado, Dattola, Adele, Fioretti, Tiziana, Esposito, Gabriella, Novelli, Antonio, Tessitore, Alessandro, Tessa, Alessandra, Santorelli, Filippo Maria, Iolascon, Achille, Monica, Matteo Della, Tartaglia, Marco, Priolo, Manuela
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2025
• Subjects: Adolescent; Adult; Adults; Aged; CES; CMA; Diagnosis; diagnostic odyssey; diagnostic yield; DNA microarrays; Exome - genetics; Exome Sequencing - methods; Female; Genetic disorders; Genetic Testing - methods; Genomics; Genomics - methods; HPO; Humans; Intellectual disabilities; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Male; Middle Aged; Patients; Rare Diseases - diagnosis; Rare Diseases - genetics; Retrospective Studies; syndromic ID; Undiagnosed Diseases - diagnosis; Undiagnosed Diseases - genetics; WES; Whole genome sequencing; Young Adult; CES; syndromic ID; WES; CMA; HPO; diagnostic yield; adults; diagnostic odyssey
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.14715

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. The diagnostic activity on 654 consecutive adult subjects presenting with molecularly unsolved conditions is reported. Definitive diagnosis was obtained in over 30% of individuals. CES/WES represented the most sensitive methodology. This study demonstrates the importance of adopting a genomic‐first approach within the diagnosis of adults affected with unsolved rare conditions.