PNRR-MR1-2022-12376811 - Implementation of a standardized workflow for a more effective management and care of patients with syndromic and isolated intellectual disability

Implementation of a standardized workflow for a more effective management and care of patients with syndromic and isolated intellectual disability

Cup C93C22009170001
Rup  Prof. Paolo Gasparini
IRCCS Burlo Garofolo
Via dell’Istria 65/1 – 34137 - Trieste
Finanziamento next generation EU

Intellectual disability (ID) affects 1-3% of the general population. Clinical manifestation of ID can occur in the form of an isolated feature or in the context of a more complex clinical phenotype (i.e., syndromic ID). ID is largely genetically determined, with 1,800 rare diseases (RDs) characterized thus far. This number represents an underestimate since a large proportion of patients (roughly 40%) still remains without an ascertained molecular cause. Subjects affected by these RDs experience diagnostic delay, which directly impacts on proper management and care. Diagnostic delay also has a relevant social and economic impact, and prevents from an appropriate genetic counseling. The unsuccessfulness of the traditional "gene-by-gene" diagnostic workup emphasizes the need of a substantial revision of the diagnostic workflow to improve both the clinical assessment and laboratory testing.

During the last decade, the use of whole exome sequencing (WES) as a first-tier diagnostic tool has significantly improved the diagnostic yield for patients with syndromic/isolated ID. Nevertheless, WES has shown to be uninformative in a significant fraction of cases. Implementation of other Omics, an improved analytical workflow directed to more effectively interpreting the genomic data, and a coordinated experimental effort pointed to solve inconclusive tests, are required to approach these challenges in a more efficient manner. Notably, establishing the clinical relevance of genomic variants still represent a major diagnostic issue, often requiring dedicated functional validation efforts.

The above considerations testify the current need of a more efficient public health policy directed to improve the whole diagnostic process. This proposal aims at implementing a standardized diagnostic workflow based on telehealth, deep phenotyping and combined/integrated Omics coupled with improvements in the bioinformatics algorithms for variant interpretation (iterative automated reannotation and identification of complex inheritance models) for a more efficient patient management and care. A strong impact in terms of both healthcare and research is anticipated. The program aims at providing a proof-of-concept for a sustainable pipeline that could be implemented in the Italian National Health System directed to improve diagnosis of syndromic/isolated ID and, more broadly, rare diseases (RDs). We also anticipate the discovery of new disease genes, and a more accurate characterization of the clinical variability and natural history of these disorders, with direct translation in the clinical practice. Finally, the project will make available new disease models and knowledge on pathophysiology to speed up basic, translational and clinical research.

Dettagli:

Missione: M6 – Salute;
Componente: M6C2 – Innovazione, ricerca e digitalizzazione del Servizio Sanitario
Investimento: 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN
Amministrazione Titolare: Ministero della Salute
Soggetto Attuatore: Ospedale pediatrico Bambino Gesù

Importo finanziato

Avanzamento del progetto

Stato di avanzamento: in corso