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

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.

Study Overview

• Status: Recruiting
• Conditions: Genetic Disease; Chopra-Amiel-Gordon Syndrome; CAGS; ANKRD17
• Intervention / Treatment: Other: Observational Study; Other: Sample collection only

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.

• Study Type: Observational
• Enrollment (Estimated): 125

Contacts and Locations

• Study Contact: Name: Abigail Sveden, MS, CGC; Phone Number: 617-919-5214; Email: Abigail.sveden@childrens.harvard.edu
• Study Contact Backup: Name: Jillian O'Toole, MS, CGC; Email: jillian.otoole@childrens.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Abigail Sveden, MS, CGC; Phone Number: 617-919-5214; Email: Abigail.sveden@childrens.harvard.edu
      • Contact: Maya Chopra, MBBS, FRACP; Phone Number: 6179196258; Email: maya.chopra@childrens.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population consists of patients of all ages and genders with a variant in ANKRD17 confirmed by pre-existing clinical genetic testing

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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.	Other: Observational Study; No intervention. This is an observational study
Unaffected family members; Family members of the proband who do not have an ANKRD17 variant.	Other: Sample collection only; Collection of blood and/or skin samples.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Investigators: Study Chair: Maya Chopra, MBBS, FRACP, Boston Children's Hospital

Publications and helpful links

General Publications

• 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.
• 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/

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2022
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: May 3, 2022
• First Submitted That Met QC Criteria: September 1, 2022
• First Posted (Actual): September 6, 2022

Study Record Updates

• Last Update Posted (Actual): February 17, 2026
• Last Update Submitted That Met QC Criteria: February 12, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Neurodevelopmental; Syndrome; Rare Disease; ANKRD17 Loss of function; ANKRD17; CAGS; Chopra-Amiel-Gordon
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Syndrome; Rare Diseases; Genetic Diseases, Inborn; Investigative Techniques; Methods; Observation
• Other Study ID Numbers: P00041124

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No