Clinical trial NCT06813469: Multi-Dimensional Genomic Dissection of Ring Chromosome 14 Syndrome
Official title: Multi-Dimensional Genomic Dissection of Ring Chromosome 14 Syndrome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Ring 14
Keywords: Ring14 Syndrome
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
First posted: 2025-02-07
Enrollment: 15
Sex: ALL
Minimum age (years): 28
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: LRS analysis of SVs occurring on chromosome 14
timeFrame: 8 months
Secondary outcomes:
measure: Genotype-phenotype correlations based on the impact of the degree of mosaicism r(14) on the ability to identify Hi-C features.
timeFrame: 8 months
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Study officials:
affiliation: IRCCS Azienda Ospedaliero-Universitaria di Bologna
name: Tommaso Pippucci, Biologist
role: PRINCIPAL_INVESTIGATOR
References: