PREcision Diagnostics in Rare genetIC Diseases and Tumors - Long Read Sequencing

NCT06796751 | Recruiting

• 2 other identifiers: PREDICT-LRSPNRR2022
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Using long-read sequencing (LRS) technology to achieve molecular diagnosis in patients with rare genetic diseases who have already been tested by state-of-the-art genetic analysis with ambiguous or negative results. This will lead to efficient and reliable identification and clinical interpretation of cryptic and complex structural genomic variants, which represent the central challenge for the coming decades in human genetics.

Conditions

Whole Exome Sequencing; Rare Diseases

Outcome Measures

Primary Outcomes (1)

• The first aim of this study is to use LRS to reach a molecular diagnosis in patients with RGD that were already tested with state-of-the-art genetic analysis, with ambiguous or negative results.

  In patients with RGD that were already tested with state-of-the-art genetic analysis, with ambiguous or negative results, will be use LRS to detect cryptic genomic variants that couldn't be detected with previous techniques. Clinical information of patients will be collected and integrated with genetic data.

  10 months

Secondary Outcomes (1)

• The secondary objective of this study is to analyze with a multi-omics approach, through the integration of other technologies supporting LRS (e.g. Hi-C, RNAseq), cases of particular complexity in which the molecular causative mechanism of the phenotype

  10 months

Study Arms (4)

Patients with CNVs of unknown significance

The first subgroup of patients are those with SVs of unknown significance or uncertain disease mechanism.

Genetic: DNA/RNA sequencing and bioinformatic data analysis

Patients with complex genomic rearrengements

Other complex rearrangements can be studied with LRS (i.e. ring chromosomes, isochromosome, chromosomal translocations, somatic SV found in tumors, etc.) to gain a better understanding of the molecular mechanisms of pathogenicity.

Genetic: DNA/RNA sequencing and bioinformatic data analysis

Patients with a monoallelic variant in an AR gene

A third subgroup of patients eligible for the study are those with identified monoallelic alteration in autosomal recessive (AR) genes.

Genetic: DNA/RNA sequencing and bioinformatic data analysis

Patients with negative results at WES analysis

Lastly, patients with a phenotype that is strongly suggestive for a genetic condition, in whom several analyses, including WES, retrieved negative results, could benefit from LRS.

Genetic: DNA/RNA sequencing and bioinformatic data analysis

Interventions

DNA/RNA sequencing and bioinformatic data analysis GENETIC

DNA will be extracted from peripheral blood or from somatic tissues. In some cases a skin biopsy will be performed to obtain fibroblasts for further analysis (DNA/RNA extraction and preparation of cell culture for high-throughput genomic and epigenomic technique (Hi-C). LRS will be performed on extracted DNA using Oxford Nanopore Technology by two different approaches: * Target, in samples with monoallelic alterations in genes related to autosomal recessive disease; * Genomic in other cases. Sequencing data will be analyzed through a dedicated bioinformatics pipeline, to reconstruct the tridimensional structure of chromatin and the regions

Patients with CNVs of unknown significance; Patients with a monoallelic variant in an AR gene; Patients with complex genomic rearrengements; Patients with negative results at WES analysis

Eligibility Criteria

• Age: 28 Days+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study population will include: * patients previously in diagnostic routine, who have provided informed consent for storage and secondary use of their biological samples and for being recontacted; they will be informed about the current project and requested to provide a new specific informed consent; * patients' parents, when segregation analysis is required for diagnostic purpose; they will be informed about the current project and requested to provide a new specific informed consent; * age: from 0 years (newborns) with no upper age limit.

You may qualify if:

• patients/relatives of patients with Copy Number Variations (CNVs), previously detected by aCGH, with uncertain clinical significance;
• patients/relatives of patients with inconclusive WES and aCGH data (no pathogenic/likely pathogenic variant);
• patients/relatives of patients with a known single hit (a pathogenic or likely pathogenic variant) in an AR gene detected with WES or aCGH;
• patients/relatives of patients with a finding of complex structural variants whose molecular disease mechanism is to be elucidated.

You may not qualify if:

• none

Sponsors & Collaborators

• IRCCS Azienda Ospedaliero-Universitaria di Bologna: lead

Study Sites (1)

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Bologna, Bologna, 40138, Italy

RECRUITING

MeSH Terms

Conditions

Rare Diseases

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Tommaso Pippucci, Biologist

  IRCCS Azienda Ospedaliero-Universitaria di Bologna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tommaso Pippucci, Biologist

CONTACT

0512142892; tommaso.pippucci@aosp.bo.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2025
• First Posted: January 28, 2025
• Study Start: October 1, 2024
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: January 31, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)