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

Official title

Characterization of the Natural History of Microduplication Syndrome

Overview

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.

Interventions

• 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.
• 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.

Primary outcome measures

• Developmental trajectory tracking through age of acquisition in months. [Time frame: At inclusion visit]
• Developmental trajectory tracking [Time frame: At inclusion visit]
• Developmental trajectory tracking [Time frame: At inclusion visit]
• Developmental trajectory tracking [Time frame: At inclusion visit]
• Developmental trajectory tracking [Time frame: At inclusion visit]
• Adaptive assessment of skills (communication, daily life, socialisation, and motor skills) [Time frame: At inclusion visit]
• Description of the global social assessment from the ADOS scale score [0-28] [Time frame: At inclusion visit]
• Description of the global autism spectrum disorder (ASD) [Time frame: At inclusion visit]

Secondary outcome measures (5)

• Full-Scale Intelligence Quotient (FSIQ) [Time frame: At inclusion visit]
• Nonverbal Intelligence Quotient (NVIQ) [Time frame: At inclusion visit]
• Epilepsy Status [Time frame: At inclusion visit]
• Atypical Sensory Profile Type [Time frame: At inclusion visit]
• 24-Hour Activity and Sleep Duration (Minutes) [Time frame: At inclusion visit]

Eligibility criteria

Inclusion criteria

• Diagnosis of 7q11.23 microduplication confirmed by Chromosomal Microarray Analysis or qPCR.
• Aged > 5 to < 50 years
• Whose maternal language is French
• Having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent.
• Affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system Each 7DUP patient will be matched to a sex- and chronological age-matched control. Data from controls will come from the CREAT\_criteria study (NCT 06018519). Each 7DUP patient will be matched to a sex- and mental age-matched control. Data from controls will come from the CREAT\_criteria study (NCT 06018519).

Exclusion criteria

• Refusal of the subject and/or the subject's parents/legal guardian to sign the informed consent
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the neuropsychological assessment.

Regarding specifically the neuroimaging data (MRI):

• Having a contraindication to the MRI examination (people using a pacemaker or an insulin pump, people wearing a metal prosthesis or an intracerebral clip, and claustrophobic subjects).
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected by MRI.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

France · 2 centers

• Developmental Anomalies Reference Center, Genetics Department Woman Mother and Child Hospi — Bron
• Reference Center of Rare Disease with Intellectual Disability- in Lyon, Woman Mother and C — Bron

Identifiers

NCT: NCT07469566 · 69HC24_0991 · 2025-A01944-45

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗