Multi-Dimensional Genomic Dissection of Ring Chromosome 14 Syndrome

MD-RING will explore the hypothesis that position effects and TAD alterations act as an unprecedented pathomechanism in r(14)S. This will contribute to a better understanding of genotype-to-phenotype correlations, creating an important scientific resource for the study of this and other ring syndromes, with the ultimate objective to offer improved family counseling , patient care and to identify potential new therapeutic options.

Study Overview

• Status: Active, not recruiting
• Conditions: Ring 14
• Intervention / Treatment: Genetic: LRS analysis

Detailed Description

Chromosome 14 ring syndrome [r(14)S] is a rare genetic disorder mainly characterized by complex and severe neurodevelopmental disorders, ranging from intellectual disability to aggressive/hyperactive behavior and drug-resistant epilepsy. Indeed, epilepsy is the most important clinical challenge in r(14)S, with enormous difficulty in controlling severe seizures and a strong need for innovative and effective treatments. Precision medicine for r(14)S patients would be greatly facilitated by knowledge of specific genes involved in pathogenesis. However, the pathophysiology of r(14)S is still largely unknown, and the identification of genotype/phenotype correlations is complicated by the co-occurrence of chromosome 14 rearrangements and the unknown degree of r(14) mosaicism in tissues most relevant to the disease. On the one hand, deletions of different sizes, from a few hundred Kbs to several Mbs, are often found in the terminal 14q region. These are an unlikely explanation for the severity and expressiveness of r(14) disease, since it has been observed that carriers of similar linear deletions of chromosome 14q rarely suffer from epilepsy. On the other hand, ring instability may promote increased monosomy of chromosome 14 in epilepsy-related areas of the brain (it is about 20% in peripheral blood).

Another fascinating hypothesis is that the mechanism and expressiveness of r(14) disease are driven primarily by the disruption of chromosome 14 conformation and positioning within the nucleus caused by its circularization, with dramatic effects on physiological interactions between genetic loci and, consequently, on gene regulation . This idea revives an unresolved question in cytogenetic disorders, whether the chromosomal abnormality itself produces a clinical phenotype beyond the pathogenic effects of the altered gene dosage. Rings can form from any chromosome, and most ring syndromes share largely similar clinical phenotypes. Severe epilepsy, for example, has been described in r(7), r(17), r(18), r(20), r(21) and r(22) syndromes in addition to r(14)S . This observation suggests that the presence of a loop within the nucleus may itself disrupt the balance of gene expression.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy, 40138
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ten LCLs of r(14)S patients with 14q deletions of varying position and extent in 70%, and monosomy 14 of varying degree in 60%.
• Five LCLs of parents without cytogenetic alterations.

Exclusion Criteria:

• Ten LCLs of r(14)S patients with 14q deletions of varying position and extent in 70%, and monosomy 14 of varying degree in 60%.
• Five LCLs of parents without cytogenetic alterations.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Lymphoblastoid Cell Lines (LCLs); 10 LCLs from r(14)S patients without other cytogenetic alterations were selected, as well as 5 LCLs from parents without cytogenetic alterations	Genetic: LRS analysis; Long Read Sequencing (LRS) and High-throughput chromosome conformation capture (Hi-C) analysis to explore and functionally characterize the r(14) event and its impact on the three-dimensional (3D) genomic architecture inside the cells of r(14)S patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LRS analysis of SVs occurring on chromosome 14	Resolving the sequence breakpoints of structural ring rearrangement in patients with r(14)S.; Construct a 3D cell-specific molecular signature of r(14)S patients.; Identify regulatory mechanisms that are important in the pathophysiology of r(14)S.	8 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Genotype-phenotype correlations based on the impact of the degree of mosaicism r(14) on the ability to identify Hi-C features.	8 months

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Investigators: Principal Investigator: Tommaso Pippucci, Biologist, IRCCS Azienda Ospedaliero-Universitaria di Bologna

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2023
• Primary Completion (Estimated): March 15, 2025
• Study Completion (Estimated): March 15, 2025

Study Registration Dates

• First Submitted: November 28, 2024
• First Submitted That Met QC Criteria: February 3, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 3, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Ring14 Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Chromosome Aberrations; Ring Chromosomes
• Other Study ID Numbers: MD-RING; RING 14 International Onlus (Other Grant/Funding Number: RING 14 International Onlus); PNRR-HEAL (Other Grant/Funding Number: MUR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No