Delineating the Molecular Spectrum and the Clinical, Imaging and Neuronal Phenotype of Chopra-Amiel-Gordon Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to establish a registry of individuals with confirmed or suspected Chopra-Amiel-Gordon Syndrome (CAGS) to learn more about the range of symptoms, changes in the structure of the brain seen on imaging, and learning difficulties that individuals with this disorder may experience. The investigators will obtain medical history, family history, MRI records, patient photographs, and genetic test results from individuals with confirmed or suspected CAGS. A subset of participants will also undergo a standardized neurobehavioral assessment. This data will be maintained on a secure research database. Sample collection will be offered to participants for the functional testing and the generation of iPSC cell lines, for neuronal reprogramming and phenotyping.

Detailed Description
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Heterozygous loss of function variants in ANKRD17 were recently implicated in a newly-identified rare intellectual disability syndrome. In an international collaborative effort spanning 4 years, the mutational and phenotypic spectrum of 34 patients were described (Chopra et al AJHG 2021). The core phenotypic features of this syndrome were shown to be intellectual disability, particularly affecting speech, and shared dysmorphic features. Variably present neurodevelopmental features were epilepsy /abnormal EEG, autism spectrum disorder, gait / balance difficulties and neuroimaging abnormalities. Extra-neurological features include growth delay, renal anomalies, hypermobility, pigmentary lesions and feeding problems. All variants were identified on whole exome or whole genome sequencing, and most were shown to be de novo and truncating, although some patients harbored missense variants particularly in highly conserved ankyrin repeat domains. While this initial project presented compelling evidence for a novel gene-disease relationship and established the key phenotypic features of this new disorder, there were limitations to this work. The neurodevelopmental profile and MRI findings were ascertained through physician report only rather than independent standardized assessment. Intriguingly, while it was observed that expressive language delay was more markedly affected than other developmental parameters, this observation was not validated with standardized patient evaluation. Currently, the impact of ANKRD17 haploinsufficiency on human neuronal morphology / excitability, and in turn, the correlation of this neuronal phenotype to the clinical neurodevelopmental profile is unknown. With this study, the investigators plan to deeply characterize the spectrum of clinical, neuroimaging and neuronal cellular features of this disorder, pairing preclinical with clinical science. The robust systematic evaluation of patients who are known or suspected to have this condition will lead to a better understanding of the true phenotypic spectrum and correlations to genotype. The inclusion of patients suspected to have CAGS, in particular, may expand the phenotypic and genotypic spectrum of the condition, and clarify diagnoses for these participants. This cross-sectional data will lay the foundations for the design of longitudinal studies and development of clinical trial endpoints. The generation of patient-specific iPSC lines and isogenic controls will allow for future projects to generate neuronal populations from clinically characterized patients, which will bridge the knowledge gap on the biological underpinnings of the disorder and potentially lead to biomarkers that reflect specific disrupted neurodevelopmental pathways.

Official Title
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Delineating the Molecular Spectrum and the Clinical, Imaging and Neuronal Phenotype of Chopra-Amiel-Gordon Syndrome

Conditions
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Genetic Disease, Chopra-Amiel-Gordon Syndrome, CAGS, ANKRD17

Intervention / Treatment
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* Other: Observational Study
* Other: Sample collection only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a known or suspected diagnosis of CAGS Participants with a known diagnosis or CAGS have a disease-causing (likely pathogenic or pathogenic) variant in ANKRD17 evidenced by a pre-existing clinical genetic report. Participants with a suspected diagnosis of CAGS must have a variant of uncertain significance in CAGS evidenced by a pre-existing clinical genetic report and clinical features of CAGS Exclusion Criteria: No evidence of a disease-causing or potentially disease-causing variant ANRKD17 variant on a pre-existing clinical genetic report.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Proband<br>Study participants who have suspected or confirmed CAGS based on having a variant of uncertain significance, likely pathogenic variant, or pathogenic variant in ANKRD17 and clinical features of the condition. | Other: Observational Study<br>* No intervention. This is an observational study<br>|
| Unaffected family members<br>Family members of the proband who do not have an ANKRD17 variant. | Other: Sample collection only<br>* Collection of blood and/or skin samples.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Research registry of molecular and phenotypic information related to CAGS | The primary endpoint of this cross-sectional natural history study will be the creation and implementation of a research registry of molecular and phenotypic information for CAGS. | 4-5 years | 
| Generation of patient-derived iPSC cell lines | An additional objective of this cross-sectional natural history study will be the generation of patient-derived iPSC cell lines. iPSC cell lines will be created from blood and skin samples of individuals with ANKRD17 variants, using samples from unaffected family members as controls. | 4-5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Syndrome, Neurodevelopmental, ANKRD17 Loss of function, ANKRD17, Rare Disease