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.
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.
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.
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.
Single group
clinical assessment
Other interventionClinical 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.
Parental questionnaires
Other interventionParental 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.
Cognitive assessment
Other interventionCognitive 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.
Reasoning assessment
DeviceSimple reasoning tasks on tablets performed at the inclusion visit.
Motor assessment
Other interventionPurdue-Pegboard test , Kinematic task and Renzi scale will be performed at inclusion visit.
Social assessment
Other interventionTwo eye-tracking tasks, ADOS, theory of mind assessment will be performed at inclusion visit.
Brain MRI (structural and functional)
Other interventionOptional brain MRI acquisition (structural and functional) will be performed at inclusion visit.
Developmental trajectory tracking through age of acquisition in months.
\- Age at head control acquisition in months,
Developmental trajectory tracking
\- Age at sitting alone in months,
Developmental trajectory tracking
\- Age at walking alone in months,
Developmental trajectory tracking
\- Age at running in months,
Full-Scale Intelligence Quotient (FSIQ)
The Full-Scale Intelligence Quotient (FSIQ) is a standardized measure of global cognitive functioning, with scores ranging from 40 to 160. It is assessed using age-appropriate Wechsler scales: Wechsler Preschool and Primary Scale of Intelligence Fourth Edition (WPPSI-IV) for children aged 5-6 years, Wechsler Intelligence Scale for Children Fifth Edition (WISC-V) for children older than 6 years, and Wechsler Adult Intelligence Scale Fourth Edition (WAIS-IV) for individuals older than 16 years. An IQ score below 70 is indicative of intellectual disability.
Nonverbal Intelligence Quotient (NVIQ)
The Nonverbal Intelligence Quotient (NVIQ) is a standardized measure of nonverbal cognitive functioning, with scores ranging from 30 to 170. It is assessed using the Leiter International Performance Scale Third Edition (Leiter-3) when Wechsler scales cannot be administered. The assessment includes four cognitive subtests to derive the nonverbal IQ score and two additional subtests evaluating nonverbal memory. An IQ score below 70 is indicative of intellectual disability.
Epilepsy Status
Epilepsy status is recorded as a dichotomous variable (Yes/No) based on information extracted from the participant's medical file at the inclusion visit. This outcome reflects the presence or absence of a documented diagnosis of epilepsy at the time of study enrollment.
Atypical Sensory Profile Type
The type of atypical sensory profile (auditory, visual, tactile, and movement-related) is determined using the Dunn Sensory Profile. This assessment is based on parent-completed questionnaires evaluating patterns of hypo- and hypersensitivity across the specified sensory domains.
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