An observational study in Neurodevelopmental Disorders, Intellectual Disability and Autism Spectrum Disorder, sponsored by Istituto Giannina Gaslini. Recruiting at 1 site in Italy. Per ClinicalTrials.gov, last updated 2026-10-20.
Sponsored by Istituto Giannina Gaslini · Observational
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.
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.
336 studies on the registry are indexed under Neurodevelopmental Disorders; 141 are open to participants now.
This study's planned enrollment of 200 is close to the median of 200 across 126 observational studies indexed under Neurodevelopmental Disorders.
Browse Neurodevelopmental Disorders studies →Istituto Giannina Gaslini is the lead sponsor of 50 studies on the registry; 33 are open to participants now.
Counted across the registry records on this site, refreshed daily.
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.
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Exclusion Criteria:
Sub-cohort 1: Patients Undergoing Genetic Data Reanalysis / Sub-cohort 2: Patients Undergoing Additional Molecular Investigations
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.
Time frame: Up to 24 months
Plan to share: 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.
No publications or documents are linked to this record.
Started Sep 2023 (actual). Primary completion is estimated for Dec 2026, 39 months after the start.
Of 64 non-industry observational studies under Neurodevelopmental Disorders, half reached primary completion within 59 months of starting (the median), counting those still running; a quarter within 40 and three quarters within 101. This study's planned 39 months is below that.
Counting every sponsor, half of 65 studies reached it within 90 months; a quarter within 40 and three quarters within 150.
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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Neurodevelopmental Disorders →
Istituto Giannina Gaslini