Abstract
Background
Whole-Exome Sequencing (WES) is a valuable tool for the molecular diagnosis of patients with a suspected genetic condition. In complex and heterogeneous diseases, the interpretation of WES variants is more challenging given the absence of diagnostic handles and other reported cases with overlapping clinical presentations.
Objective
To describe candidate variants emerging from trio-WES and possibly associated with the clinical phenotype in clinically heterogeneous conditions.
Methods
We performed WES in ten patients from eight families, selected because of the lack of a clear clinical diagnosis or suspicion, the presence of multiple clinical signs, and the negative results of traditional genetic tests.
Results
Although we identified ten candidate variants, reaching the diagnosis of these cases is challenging, given the complexity and the rarity of these syndromes and because affected genes are already associated with known genetic diseases only partially recapitulating patients’ phenotypes. However, the identification of these variants could shed light into the definition of new genotype–phenotype correlations. Here, we describe the clinical and molecular data of these cases with the aim of favoring the match with other similar cases and, hopefully, confirm our diagnostic hypotheses.
Conclusion
This study emphasizes the major limitations associated with WES data interpretation, but also highlights its clinical utility in unraveling novel genotype–phenotype correlations in complex and heterogeneous undefined clinical conditions with a suspected genetic etiology.
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Availability of data and materials
The data that support the findings of this study are available from the corresponding author, Prof. Monica Rosa Miozzo, upon reasonable request.
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Acknowledgements
We would like to thank the probands and their families for adhering to the study and giving consent to publish their data, as well as the clinical investigators and research staff (in particular Erica Rosina, Benedetta Beltrami, Federica Gaudioso and Diana Simpatico) for their participation in the “CARE: Challenging Approaches to undiagnosed Rare diseases with Exome sequencing” project. The project was granted by Scientific Direction, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan.
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GM, OR, AM, CP: WES data analysis and interpretation, and manuscript drafting. JC: bioinformatic analysis. CS, PC: WES and Sanger experiments. EM, GM, FG, BR, EP, GS, RV, MFB, DM: clinical evaluation and patient follow-up. MRM, LF: project supervision and contribution to result interpretation.
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All authors (Giada Moresco, Ornella Rondinone, Alessia Mauri, Jole Costanza, Carlo Santaniello, Patrizia Colapietro, Emanuele Micaglio, Giovanni Marfia, Federico Grilli, Berardo Rinaldi, Elisabetta Prada, Giulietta Scuvera, Roberta Villa, Maria Francesca Bedeschi, Monica Rosa Miozzo, Donatella Milani and Laura Fontana) declare that they have no conflict of interest.
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Moresco, G., Rondinone, O., Mauri, A. et al. Pitfalls of whole exome sequencing in undefined clinical conditions with a suspected genetic etiology. Genes Genom 45, 637–655 (2023). https://doi.org/10.1007/s13258-022-01341-x
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DOI: https://doi.org/10.1007/s13258-022-01341-x