Precision Diagnosis and Therapy for Rare Diseases by Interpreting Non-coding Genomes

Condition(s) studied

Investigational drug(s) / intervention(s)

PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy.: Samples are collected by UO1/UO2/UO3. DNA/RNA samples are sent to UO3 for genome and transcriptome sequencing. In vitro systems or patient-derived cell models are used for in vitro experimental validation (UO2) or development of therapeutical approaches (UO2/UO4). Samples of cases still undiagnosed after the combined sequencing and validation approaches undergo long-read sequencing by an outsourcing facility. Sequencing data are transferred to UO1 for bioinformatic analysis and may be deposited into RDconnect for still inconclusive cases. Variants of interest from bioinformatic analyses and in vitro validations are collectively discussed by UO1/UO2/UO3 to evaluate their clinico-molecular significance and to be selected for testing therapeutic approaches by UO2/UO4. Blue arrows and shapes denote samples and personal data, while green data that make no identifiable person.

Study summary

PARADIGM study, funded by the PNRR research grant, will focus on Eye Diseases (ED) and Neuro-Muscular Diseases (NMD) as groups of genetically heterogeneous diseases which are extensively studied by the Partners partecipating in the project; indeed ED and NMD are well clinically and molecularly characterized and approachable by drug-testing options already assessed and implemented by PARADIGM partners. ED and NMD represent good and compatible disease models as:

* both are genetically heterogeneous disorders where missing heritability is likely to be hidden in non-coding variants;
* many of the individual genes accountable for the ED and NMD cause autosomal recessive forms, increasing the chance of finding regulatory/splicing variants

Eligibility

Primary outcome measure(s)

• Identification of genomic variants — 22 months
  To efficiently and reliably identify, and clinically interpret, cryptic genomic variants, representing the central challenge for the next decades of human genetics. The study will focus on ED and NMD conditions. The Diagnostic yield will be calculated as the proportion of the diagnosed cases over the total cases. Cases will be considered to be diagnosed when pathogenic or likely pathogenic genotype(s) will be identified and will be consistent with the patients clinical phenotype and segregation in the family.

Trial sites (1)

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