Whole Exome SequencingPREDICT-LRSNCT06796751
PREcision Diagnostics in Rare genetIC Diseases and Tumors - Long Read Sequencing
An observational study of Whole Exome Sequencing and Rare Diseases, run by IRCCS Azienda Ospedaliero-Universitaria di Bologna at 1 site in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 28 days and older
- Conditions the study is for
- Whole Exome Sequencing, Rare Diseases
- What is being tested?
- DNA/RNA sequencing and bioinformatic data analysis
- How many people
- 30 participants
- Where
- 1 siteItaly
- Study dates
- 1 Oct 2024to 30 Sep 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 28 days and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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.
Who may be able to join
- 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.
Who cannot join
- none
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Bologna, Bologna, 40138
Tommaso Pippucci, Biologist, 0512142892, tommaso.pippucci@aosp.bo.it
Tommaso Pippucci, Biologist
About this study
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.
Read the detailed description
The application of LRS to a diagnostic setting could have an impact on detection rate and diagnostic yield, leading to a better understanding of the etiology, prognosis and recurrence risk of rare genetic diseases (RGD), but also to a targeted treatment. One of the main benefits of LRS is the detection of balanced and unbalanced structural variants (SVs), including complex rearrangements, with high sensitivity and accuracy, through reliable alignment and precise breakpoint definition.
Among the main challenges of modern genetics, are identified 4 subgroups of patients that would benefit from the application of LRS to better characterize the genetic diagnosis and disease mechanisms.
- The first subgroup of patients are those with SVs of unknown significance or uncertain disease mechanism. In particular, clinical interpretation of duplications is challenging, due to the inability of Array Comparative Genomic Hybridization (aCGH) to detect whether they occur in tandem or are duplicated and inserted elsewhere in the genome, thus possibly disrupting genes involved in the duplication or altering their regulation.
- Other complex rearrangements can be studied with LRS to gain a better understanding of the molecular mechanisms of pathogenicity. A better definition of complex SVs, together with an accurate description of the phenotype, will allow the genotype-phenotype correlation to be determined.
- A third subgroup of patients eligible for the study are those with identified monoallelic alteration in autosomal recessive (AR) genes. The aim is to conduct a targeted analysis of the specific gene in order to look for a second mutation that wasn't detected by previous analysis (i.e. intronic variants, SVs, variants in difficult genomic regions).
- Lastly, patients with a phenotype that is strongly suggestive for a genetic condition, in whom several analyses, including Whole Exome-Sequencing (WES), retrieved negative results, could benefit from LRS. In this context, the aim is to apply a whole genome LRS approach to identify missed coding variants in difficult-to-sequence regions, variants in non-coding regions or SVs.
- Conditions
- Whole Exome Sequencing, Rare Diseases
- Being tested
- DNA/RNA sequencing and bioinformatic data analysis
- Medical subject headings
- Rare Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DNA/RNA sequencing and bioinformatic data analysisGenetic
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
| Study group | Role | What they receive |
|---|---|---|
| Patients with CNVs of unknown significance | The first subgroup of patients are those with SVs of unknown significance or uncertain disease mechanism. Receives: 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. Receives: 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. Receives: 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. Receives: Genetic: DNA/RNA sequencing and bioinformatic data analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Definition and precise characterization of structural variants and complex rearrangements with implication for their molecular diagnosis and clinical management.
Measured: 10 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2025
- Study start1 Oct 2024
- Primary completion30 Sep 2026 (estimated)
- Study completion30 Sep 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Whole Exome SequencingStudies of the same condition, open and under way.
- More trials run by IRCCS Azienda Ospedaliero-Universitaria di BolognaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Tommaso Pippucci, Biologist, Principal investigator, IRCCS Azienda Ospedaliero-Universitaria di Bologna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06796751
- Sponsor's protocol ID
- PREDICT-LRS
- Other IDs
- PNRR2022
- Acronym
- PREDICT-LRS
- Status last verified
- Dec 2024
- First submitted
- 22 Jan 2025
- Last updated
- 31 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PREcision Diagnostics in Rare genetIC Diseases and Tumors - Long Read Sequencing
- ClinicalTrials.gov ID
- NCT06796751
- Acronym / sponsor ID
- PREDICT-LRS / PREDICT-LRS
- Conditions
- Whole Exome Sequencing, Rare Diseases
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- IRCCS Azienda Ospedaliero-Universitaria di BolognaUniversity, hospital or other
- Study start
- 1 Oct 2024 (actual)
- Primary completion
- 30 Sep 2026 (estimated)
- Study completion
- 30 Sep 2026 (estimated)
- First posted
- 28 Jan 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
The application of LRS to a diagnostic setting could have an impact on detection rate and diagnostic yield, leading to a better understanding of the etiology, prognosis and recurrence risk of rare genetic diseases (RGD), but also to a targeted treatment. One of the main benefits of LRS is the detection of balanced and unbalanced structural variants (SVs), including complex rearrangements, with high sensitivity and accuracy, through reliable alignment and precise breakpoint definition.
Among the main challenges of modern genetics, are identified 4 subgroups of patients that would benefit from the application of LRS to better characterize the genetic diagnosis and disease mechanisms.
- The first subgroup of patients are those with SVs of unknown significance or uncertain disease mechanism. In particular, clinical interpretation of duplications is challenging, due to the inability of Array Comparative Genomic Hybridization (aCGH) to detect whether they occur in tandem or are duplicated and inserted elsewhere in the genome, thus possibly disrupting genes involved in the duplication or altering their regulation.
- Other complex rearrangements can be studied with LRS to gain a better understanding of the molecular mechanisms of pathogenicity. A better definition of complex SVs, together with an accurate description of the phenotype, will allow the genotype-phenotype correlation to be determined.
- A third subgroup of patients eligible for the study are those with identified monoallelic alteration in autosomal recessive (AR) genes. The aim is to conduct a targeted analysis of the specific gene in order to look for a second mutation that wasn't detected by previous analysis (i.e. intronic variants, SVs, variants in difficult genomic regions).
- Lastly, patients with a phenotype that is strongly suggestive for a genetic condition, in whom several analyses, including Whole Exome-Sequencing (WES), retrieved negative results, could benefit from LRS. In this context, the aim is to apply a whole genome LRS approach to identify missed coding variants in difficult-to-sequence regions, variants in non-coding regions or SVs.
Study design
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Patients with CNVs of unknown significance | – | Genetic: DNA/RNA sequencing and bioinformatic data analysisThe first subgroup of patients are those with SVs of unknown significance or uncertain disease mechanism. |
| Patients with complex genomic rearrengements | – | Genetic: DNA/RNA sequencing and bioinformatic data analysisOther 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. |
| Patients with a monoallelic variant in an AR gene | – | Genetic: DNA/RNA sequencing and bioinformatic data analysisA third subgroup of patients eligible for the study are those with identified monoallelic alteration in autosomal recessive (AR) genes. |
| Patients with negative results at WES analysis | – | Genetic: DNA/RNA sequencing and bioinformatic data analysisLastly, 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. |
Who may qualify
- Ages
- 28 days and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- 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.
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (1 listed)
- none
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DNA/RNA sequencing and bioinformatic data analysisDNA 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 | Genetic | 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 |
Primary outcome
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.
Time frame: 10 months
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.
1 secondary outcome
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
Time frame: 10 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Tommaso Pippucci, Biologist principal investigator
IRCCS Azienda Ospedaliero-Universitaria di Bologna
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Whole Exome Sequencing and Rare Diseases, run by IRCCS Azienda Ospedaliero-Universitaria di Bologna at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 31 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Tommaso Pippucci, Biologist (0512142892, tommaso.pippucci@aosp.bo.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: 10 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2025.