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

Overview

The purpose of this study is to establish the longitudinal natural history 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, genetic test results, neurobehavioral and quality of life questionnaires from individuals with confirmed or suspected CAGS at annual research visits. Participants may also complete standardized research neurobehavioral assessments, research EEGs, and sample collections at each visit. This data will be maintained on a secure research database. Samples collected will be used for functional testing and the generation of iPSC cell lines, for neuronal reprogramming and phenotyping.

Detailed description

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 longitudinal spectrum of clinical, neuroimaging and neuronal cellular features of this disorder, pairing preclinical with clinical science. The robust annual 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 with ANKRD17 VUS and/or suspected to have CAGS, in particular, may expand the phenotypic and genotypic spectrum of the condition, and clarify diagnoses for these participants. 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.

Interventions

• Other Observational Study
  No intervention. This is an observational study
• Other Sample collection only
  Collection of blood and/or skin samples.

Primary outcome measures

• Research registry of molecular and phenotypic information related to CAGS [Time frame: 4-5 years]
• Generation of patient-derived iPSC cell lines [Time frame: 4-5 years]

Eligibility criteria

Inclusion criteria

• Participants must have a variant in ANKRD17 with a classification of VUS, likely pathogenic, or pathogenic
• 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 ANKRD17 evidenced by a pre-existing clinical genetic report and clinical features of CAGS
• Participants with a VUS in ANKRD17 must have a variant of uncertain significance in ANKRD17

Exclusion criteria

• No evidence of a disease-causing or potentially disease-causing variant ANRKD17 variant on a pre-existing clinical genetic report.

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

Healthy volunteers: No

Study design

Observational model

Other

Study locations

United States · 1 center

• Boston Children's Hospital — Boston

Publications

• Sveden A, Gordon CT, Amiel J, Chopra M. ANKRD17-Related Neurodevelopmental Syndrome. 2022 Dec 22. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK588029/ PMID 36548456
• Chopra M, McEntagart M, Clayton-Smith J, Platzer K, Shukla A, Girisha KM, Kaur A, Kaur P, Pfundt R, Veenstra-Knol H, Mancini GMS, Cappuccio G, Brunetti-Pierri N, Kortum F, Hempel M, Denecke J, Lehman A; CAUSES Study; Kleefstra T, Stuurman KE, Wilke M, Thompson ML, Bebin EM, Bijlsma EK, Hoffer MJV, Peeters-Scholte C, Slavotinek A, Weiss WA, Yip T, Hodoglugil U, Whittle A, diMonda J, Neira J, Yang S PMID 33909992

Identifiers

NCT: NCT05528744 · P00041124

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗