Characterization of the Natural History of Microduplication Syndrome 7q11.23

Summary

7q11.23 duplication syndrome (7q duplication syndrome/7DUP) is caused by a microduplication of the 7q11.23 chromosomal region, encompassing 26-28 genes, including the GTF2I gene. This syndrome, often considered as a "mirror" phenotype of Williams-Beuren syndrome (WBS), is characterized by a wide range of neurodevelopmental impairments, including a neurodevelopmental disorder (NDD), autism spectrum disorders (ASD), selective mutism, mild dysmorphic features, and aortic dilation. Notably, one of the core clinical features of 7DUP is socialization impairment, which varies in severity across individuals.

The GTF2I gene, identified as critical in the pathogenesis of both WBS and 7DUP, exhibits opposite expression patterns in the two syndromes, with reduced expression in WBS and overexpression in 7DUP. The gene's dysregulation in 7DUP plays a pivotal role in the pathogenesis of the associated NDD and social deficits. Despite progress in characterizing the genetic underpinnings of 7DUP, there remains a critical gap in understanding the developmental trajectory of socialization impairments in affected individuals, especially during their transition through different developmental stages, from early childhood to adulthood.

Recent advancements in the study of neuronal models derived from induced pluripotent stem cells (iPSCs) and brain organoids have shed light on the molecular mechanisms driving 7DUP-related NDDs. Histone deacetylase inhibitors (HDAC inhibitors), which have been widely used in oncology, have shown promising preliminary results in reducing abnormal GTF2I expression in glutamatergic neurons differentiated from 7DUP patient-derived iPSCs. Preclinical studies in mouse models further demonstrated that these drugs can ameliorate socialization deficits, highlighting their therapeutic potential in addressing the core neurodevelopmental challenges in 7DUP.

However, despite these advancements, no longitudinal clinical studies have characterized the developmental trajectory of socialization impairments in 7DUP patients. Understanding this trajectory is critical, as it can inform the timing and potential impact of therapeutic interventions, such as HDAC inhibitors. Given the complexity and variability of the 7DUP phenotype, a comprehensive clinical characterization of socialization impairments across the lifespan is essential to improve diagnostic accuracy, optimize intervention strategies, and ultimately improve patient outcomes.

The aim of this research is to characterize the developmental trajectory of socialization impairments in patients with 7DUP, from early childhood through adulthood. By identifying patterns of socialization difficulties, this innovative study will allow to efficiently prepare future therapeutic trials, by specifying the phenotype of the patients, and by determining the most relevant outcome measures, taking into account, on one hand, their neurodevelopmental involvement and, on the other hand, the type of experimental design to be used in the context of rare diseases.

Conditions

• 7q11.23 Microduplication Syndrome (7DUP)
• Autism Spectrum Disorder (ASD)
• Neurodevelopmental Disorders (NDD)

Interventions

OTHER

Social assessment

Two eye-tracking tasks, ADOS, theory of mind assessment will be performed at inclusion visit.

OTHER

Brain MRI (structural and functional)

Optional brain MRI acquisition (structural and functional) will be performed at inclusion visit.

OTHER

clinical assessment

Clinical examination including Medical history, developmental trajectory, epilepsy history, clinical examination, actimetry over 24hours, podometry, 6 minutes walk test at the inclusion visit by a neuropediatrist.

OTHER

Parental questionnaires

Parental questionnaires including Vineland Adaptive Behavior scale second edition (Vineland II) , SRS-2, CBI, Beach Center Family Quality Of Life , PPD-MRS, Dunn sensory profile, ABC, Nisonger Child Behavior Rating, PEDSQL, Pediatric Quality of Life Inventory , San Martin Scale completed at the inclusion visit.

OTHER

Cognitive assessment

Cognitive assessment including Leiter-3, Bayley-4 (if Leiter-3 not possible), CPM-BF, 4 sub-tests from the WPPSI-IV, 4 sub-tests from KITAP.PPVT 5, EVT 3, EXALANG 3-6 and automatic language analysis will be performed at the inclusion visit.

DEVICE

Reasoning assessment

Simple reasoning tasks on tablets performed at the inclusion visit.

OTHER

Motor assessment

Purdue-Pegboard test , Kinematic task and Renzi scale will be performed at inclusion visit.

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Study Design

Allocation

NA

Purpose

OTHER

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

5 Years

Max Age

50 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-07-15

Primary Completion

2028-01-01

Completion

2028-01-01

Countries

• France

Study Locations