Neurodevelopmental DisordersLEOPARDNCT07884227
Multi-Omics Genetic Investigation Strategies to Enhance the Diagnostic Workflow for Rare Diseases
An observational study of Neurodevelopmental Disorders and Intellectual Disability, run by Istituto Giannina Gaslini at 1 site in Italy.
Trial summary
LEOPARD is a multicenter study aimed at improving the genetic diagnosis of patients with neurodevelopmental disorders (NDDs) of unknown etiology, particularly those with moderate-to-severe intellectual disability. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Neurodevelopmental Disorders, Intellectual Disability, Autism Spectrum Disorder
- How many people
- 200 participants
- Where
- 1 siteItaly
- Study dates
- 4 Sep 2023to Jun 2027
- 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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: The study population will include patients with autism spectrum disorder and/or other neurodevelopmental disorders, particularly those with moderate-to-severe intellectual disability (IQ below 50) of unknown genetic etiology. The initial cohort will consist of patients previously investigated by chromosomal microarray analysis (CMA) and/or exome sequencing (ES). Patients who remain undiagnosed after genetic data reanalysis will be considered for additional molecular investigations. Additional participants may be recruited if required to achieve the planned sample size for the second phase.
Who may be able to join
- Diagnosis of autism spectrum disorder and/or another neurodevelopmental disorder.
- Moderate-to-severe intellectual disability, documented by psychometric assessment, with an intelligence quotient (IQ) below 50.
- Previous genetic testing by chromosomal microarray analysis (CMA) and/or exome sequencing (ES).
- Availability and willingness to provide biological samples, including peripheral blood, saliva, and urine, as required for the planned molecular investigations.
- Availability of parental biological samples, whenever feasible.
Who cannot join
- An established clinical diagnosis that already explains the participant's clinical presentation.
- Intellectual disability of a known non-genetic etiology, such as perinatal hypoxia.
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 Istituto Giannina Gaslini
Genova, 16147
Aldamaria Puliti, MD, PhD, +3901056362802, aldamariapuliti@gaslini.org
Valeria Antenucci, MD, +3901056363128, valeriaantenucci@gaslini.org
About this study
LEOPARD is a multicenter study aimed at improving the genetic diagnosis of patients with neurodevelopmental disorders (NDDs) of unknown etiology, particularly those with moderate-to-severe intellectual disability. The study combines reanalysis of previously generated genetic data with additional molecular investigations, including functional validation of variants of uncertain significance, RNA sequencing, and DNA methylation profiling. The project also aims to develop a computational infrastructure to support data reanalysis, integration, storage, and sharing, thereby improving the diagnostic workflow for rare diseases and supporting personalized patient care.
Read the detailed description
Neurodevelopmental disorders (NDDs) represent a major group of rare diseases and are frequently associated with substantial morbidity due to underlying genetic alterations. Despite advances in genetic testing, chromosomal microarray analysis (CMA) and exome sequencing (ES) identify a causal genetic diagnosis in only approximately 30-40% of affected individuals. The remaining diagnostic gap may reflect both the limitations of current methods in detecting certain types of genetic alterations and the difficulty of determining the clinical significance of identified variants.
The LEOPARD project aims to improve diagnostic yield in patients with NDDs of unknown genetic etiology through a two-phase approach.
Phase 1: Reanalysis of existing genetic data. Genetic data from 500 patients previously investigated by ES or CMA will be reanalyzed using updated bioinformatics algorithms and current biomedical knowledge. Some patients have already provided consent for the use of their genomic and clinical data in previous studies conducted at the participating clinical centers. The remaining patients will be contacted to obtain informed consent for the use of their data. Approximately one-third of these patients are expected to receive a genetic diagnosis through data reanalysis alone.
Phase 2: Additional molecular investigations. Up to 200 patients who remain undiagnosed after data reanalysis will undergo further molecular investigations, selected according to the clinical and technical eligibility criteria for each test. These investigations will include functional studies to assess the clinical significance of variants of uncertain significance, RNA sequencing to evaluate gene expression and transcript integrity, and DNA methylation profiling to identify disease-associated methylation signatures (episignatures).
If the number of eligible patients remaining undiagnosed after Phase 1 is insufficient, additional patients will be recruited through the participating clinical centers. This phase will require the collection of new biological samples using minimally invasive procedures, including peripheral blood sampling and the collection of buccal and urinary epithelial cells. Biological samples will be sent to the appropriate laboratories according to the analyses required and stored in the study biobanks.
Genetic alterations and identified variants will be evaluated according to applicable national and international scientific guidelines, including recommendations from the Italian Society of Human Genetics (SIGU) and the American College of Medical Genetics and Genomics (ACMG).
The diagnostic contribution of each additional molecular investigation will be assessed using statistical methods to estimate the improvement in diagnostic sensitivity and overall diagnostic yield.
The project will run for 24 months and will involve three clinical and laboratory units and one bioinformatics unit. The participating centers have the clinical expertise and patient population required to support recruitment in accordance with the study objectives.
- Conditions
- Neurodevelopmental Disorders, Intellectual Disability, Autism Spectrum Disorder, Genetic Diseases, Inborn
- Keywords
- Rare Diseases, Neurodevelopmental Disorders, Intellectual Disability, Autism Spectrum Disorder, Genetic Diagnosis, Genetic Testing, Exome Sequencing, Chromosomal Microarray Analysis, RNA Sequencing, DNA Methylation, Epigenomics, Variants of Uncertain Significance, Diagnostic Yield, Bioinformatics, Precision Medicine
- Medical subject headings
- Neurodevelopmental Disorders, Intellectual Disability, Autism Spectrum Disorder, Genetic Diseases, Inborn, Rare Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Patients with Undiagnosed Neurodevelopmental Disorders - | Sub-cohort 1: Patients Undergoing Genetic Data Reanalysis / Sub-cohort 2: Patients Undergoing Additional Molecular Investigations |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of Participants Receiving a Genetic Diagnosis
Proportion of participants in whom a specific genetic diagnosis is established following reanalysis of existing genetic data and, where applicable, additional molecular investigations. The diagnostic yield will be assessed by identifying the proportion of participants receiving a genetic diagnosis among those evaluated.
Measured: Up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Oct 2026
- Study start4 Sep 2023
- Primary completion31 Dec 2026 (estimated)
- Study completionJun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Neurodevelopmental DisordersStudies of the same condition, open and under way.
- 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
- Case only
- Time perspective
- Other
- Enrolment
- 200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Istituto Giannina Gaslini
- Sponsor type
- University, hospital or other
- Collaborators
- Ministry of Health, Italy
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07884227
- Sponsor's protocol ID
- PNRR-MR1-2022-12376067
- Acronym
- LEOPARD
- Status last verified
- Oct 2026
- First submitted
- 13 Oct 2026
- Last updated
- 20 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Individual participant data (IPD) may be shared with qualified researchers for research purposes related to rare genetic diseases and neurodevelopmental disorders, subject to applicable ethical approvals, informed consent provisions, and data protection requirements. Data will be pseudonymized before sharing, where applicable. Requests for access will be reviewed by the study investigators to ensure that the proposed use is consistent with the study objectives, participant consent, and applicable regulations. Biological samples and identifiable personal data will not be shared unless specifically authorized under the applicable consent and regulatory framework.
Study at a glance
From the registry record, last updated by the sponsor on 20 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Multi-Omics Genetic Investigation Strategies to Enhance the Diagnostic Workflow for Rare Diseases
- ClinicalTrials.gov ID
- NCT07884227
- Acronym / sponsor ID
- LEOPARD / PNRR-MR1-2022-12376067
- Conditions
- Neurodevelopmental Disorders, Intellectual Disability, Autism Spectrum Disorder, Genetic Diseases, Inborn
- Keywords
- Rare Diseases, Neurodevelopmental Disorders, Intellectual Disability, Autism Spectrum Disorder, Genetic Diagnosis, Genetic Testing, Exome Sequencing, Chromosomal Microarray Analysis
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- Istituto Giannina GasliniUniversity, hospital or other
- Collaborators
- Ministry of Health, Italy
- Study start
- 4 Sep 2023 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- Jun 2027 (estimated)
- First posted
- 20 Oct 2026 (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.
LEOPARD is a multicenter study aimed at improving the genetic diagnosis of patients with neurodevelopmental disorders (NDDs) of unknown etiology, particularly those with moderate-to-severe intellectual disability. The study combines reanalysis of previously generated genetic data with additional molecular investigations, including functional validation of variants of uncertain significance, RNA sequencing, and DNA methylation profiling. The project also aims to develop a computational infrastructure to support data reanalysis, integration, storage, and sharing, thereby improving the diagnostic workflow for rare diseases and supporting personalized patient care.
Detailed description
Neurodevelopmental disorders (NDDs) represent a major group of rare diseases and are frequently associated with substantial morbidity due to underlying genetic alterations. Despite advances in genetic testing, chromosomal microarray analysis (CMA) and exome sequencing (ES) identify a causal genetic diagnosis in only approximately 30-40% of affected individuals. The remaining diagnostic gap may reflect both the limitations of current methods in detecting certain types of genetic alterations and the difficulty of determining the clinical significance of identified variants.
The LEOPARD project aims to improve diagnostic yield in patients with NDDs of unknown genetic etiology through a two-phase approach.
Phase 1: Reanalysis of existing genetic data. Genetic data from 500 patients previously investigated by ES or CMA will be reanalyzed using updated bioinformatics algorithms and current biomedical knowledge. Some patients have already provided consent for the use of their genomic and clinical data in previous studies conducted at the participating clinical centers. The remaining patients will be contacted to obtain informed consent for the use of their data. Approximately one-third of these patients are expected to receive a genetic diagnosis through data reanalysis alone.
Phase 2: Additional molecular investigations. Up to 200 patients who remain undiagnosed after data reanalysis will undergo further molecular investigations, selected according to the clinical and technical eligibility criteria for each test. These investigations will include functional studies to assess the clinical significance of variants of uncertain significance, RNA sequencing to evaluate gene expression and transcript integrity, and DNA methylation profiling to identify disease-associated methylation signatures (episignatures).
If the number of eligible patients remaining undiagnosed after Phase 1 is insufficient, additional patients will be recruited through the participating clinical centers. This phase will require the collection of new biological samples using minimally invasive procedures, including peripheral blood sampling and the collection of buccal and urinary epithelial cells. Biological samples will be sent to the appropriate laboratories according to the analyses required and stored in the study biobanks.
Genetic alterations and identified variants will be evaluated according to applicable national and international scientific guidelines, including recommendations from the Italian Society of Human Genetics (SIGU) and the American College of Medical Genetics and Genomics (ACMG).
The diagnostic contribution of each additional molecular investigation will be assessed using statistical methods to estimate the improvement in diagnostic sensitivity and overall diagnostic yield.
The project will run for 24 months and will involve three clinical and laboratory units and one bioinformatics unit. The participating centers have the clinical expertise and patient population required to support recruitment in accordance with the study objectives.
Study design
- Observational model
- Case only
- Time perspective
- Other
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with Undiagnosed Neurodevelopmental Disorders - | – | –Sub-cohort 1: Patients Undergoing Genetic Data Reanalysis / Sub-cohort 2: Patients Undergoing Additional Molecular Investigations |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- The study population will include patients with autism spectrum disorder and/or other neurodevelopmental disorders, particularly those with moderate-to-severe intellectual disability (IQ below 50) of unknown genetic etiology. The initial cohort will consist of patients previously investigated by chromosomal microarray analysis (CMA) and/or exome sequencing (ES). Patients who remain undiagnosed after genetic data reanalysis will be considered for additional molecular investigations. Additional participants may be recruited if required to achieve the planned sample size for the second phase.
Key inclusion criteria (5 listed)
- Diagnosis of autism spectrum disorder and/or another neurodevelopmental disorder.
- Moderate-to-severe intellectual disability, documented by psychometric assessment, with an intelligence quotient (IQ) below 50.
- Previous genetic testing by chromosomal microarray analysis (CMA) and/or exome sequencing (ES).
- Availability and willingness to provide biological samples, including peripheral blood, saliva, and urine, as required for the planned molecular investigations.
- Availability of parental biological samples, whenever feasible.
Key exclusion criteria (2 listed)
- An established clinical diagnosis that already explains the participant's clinical presentation.
- Intellectual disability of a known non-genetic etiology, such as perinatal hypoxia.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Proportion of Participants Receiving a Genetic Diagnosis
Time frame: Up to 24 months
Proportion of participants in whom a specific genetic diagnosis is established following reanalysis of existing genetic data and, where applicable, additional molecular investigations. The diagnostic yield will be assessed by identifying the proportion of participants receiving a genetic diagnosis among those evaluated.
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 20 Oct 2026.
- Individual participant dataSharing planned: Undecided. Individual participant data (IPD) may be shared with qualified researchers for research purposes related to rare genetic diseases and neurodevelopmental disorders, subject to applicable ethical approvals, informed consent provisions, and data protection requirements. Data will be pseudonymized before sharing, where applicable. Requests for access will be reviewed by the study investigators to ensure that the proposed use is consistent with the study objectives, participant consent, and applicable regulations. Biological samples and identifiable personal data will not be shared unless specifically authorized under the applicable consent and regulatory framework.
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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.
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 Neurodevelopmental Disorders and Intellectual Disability, run by Istituto Giannina Gaslini 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 5 inclusion and 2 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 20 Oct 2026. 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 Aldamaria Puliti, MD, PhD (+3901056362802, aldamariapuliti@gaslini.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of Participants Receiving a Genetic Diagnosis (time frame: Up to 24 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 20 Oct 2026.