Clinical trial NCT05528744: Delineating the Molecular Spectrum and the Clinical, Imaging and Neuronal Phenotype of Chopra-Amiel-Gordon Syndrome
Official title: Delineating the Molecular Spectrum and the Clinical, Imaging and Neuronal Phenotype of Chopra-Amiel-Gordon Syndrome
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Genetic Disease
Chopra-Amiel-Gordon Syndrome
CAGS
ANKRD17
Keywords: Syndrome
Neurodevelopmental
ANKRD17 Loss of function
ANKRD17
Rare Disease
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
First posted: 2022-09-06
Enrollment: 60
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population consists of patients of all ages and genders with a confirmed or suspected diagnosis of CAGS confirmed by pre-existing clinical genetic testing

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.

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.

Primary outcomes:
measure: Research registry of molecular and phenotypic information related to CAGS
timeFrame: 4-5 years
measure: Generation of patient-derived iPSC cell lines
timeFrame: 4-5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
Study officials:
affiliation: Boston Children's Hospital
name: Abigail Sveden, MS, CGC
role: STUDY_CHAIR
References:
citation: 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.