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

NCT ID: NCT05528744

Last Updated: 2023-10-23

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-08-27
• Study Completion Date: 2026-12-01

Brief Summary

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

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.

Conditions

Genetic Disease; Chopra-Amiel-Gordon Syndrome; CAGS; ANKRD17

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Proband

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.

Observational Study

Intervention Type: OTHER

No intervention. This is an observational study

Unaffected family members

Family members of the proband who do not have an ANKRD17 variant.

Sample collection only

Intervention Type: OTHER

Collection of blood and/or skin samples.

Interventions

Observational Study

No intervention. This is an observational study

Intervention Type: OTHER

Sample collection only

Collection of blood and/or skin samples.

Intervention Type: OTHER

Eligibility Criteria

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.

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Maya Chopra

Director of Translational Genomic Medicine, Rosamund Stone Zander Translational Neuroscience Centre at Boston Children's Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Abigail Sveden, MS, CGC

Role: STUDY_CHAIR

Boston Children's Hospital

Locations

Boston Children's Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Maya Chopra, MBBS FRACP

Role: CONTACT

maya.chopra@childrens.harvard.edu

617-919-6258

Raymond Belanger Deloge, MS, CGC

Role: CONTACT

Raymond.belangerdeloge@childrens.harvard.edu

Facility Contacts

Maya Chopra, MBBS, FRACP

Role: primary

maya.chopra@childrens.harvard.edu

617-919-6258

Raymond Belanger Deloge, MS, CGC

Role: backup

Raymond.belangerdeloge@childrens.harvard.edu

References

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, Kirby A, Pinz H, Lechner R, Sleutels F, Helbig I, McKeown S, Helbig K, Willaert R, Juusola J, Semotok J, Hadonou M, Short J; Genomics England Research Consortium; Yachelevich N, Lala S, Fernandez-Jaen A, Pelayo JP, Klockner C, Kamphausen SB, Abou Jamra R, Arelin M, Innes AM, Niskakoski A, Amin S, Williams M, Evans J, Smithson S, Smedley D, de Burca A, Kini U, Delatycki MB, Gallacher L, Yeung A, Pais L, Field M, Martin E, Charles P, Courtin T, Keren B, Iascone M, Cereda A, Poke G, Abadie V, Chalouhi C, Parthasarathy P, Halliday BJ, Robertson SP, Lyonnet S, Amiel J, Gordon CT. Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism. Am J Hum Genet. 2021 Jun 3;108(6):1138-1150. doi: 10.1016/j.ajhg.2021.04.007. Epub 2021 Apr 27.

Reference Type: BACKGROUND

PMID: 33909992 (View on PubMed)

Other Identifiers

P00041124

Identifier Type: -

Identifier Source: org_study_id