[article]
| Titre : |
Longitudinal characterization of clinical, developmental, and behavioral phenotypes in 101 children and adults with FOXG1 syndrome |
| Type de document : |
texte imprimé |
| Auteurs : |
Elise BRIMBLE, Auteur ; Pam VENTOLA, Auteur ; Elizabeth BLOMENBERG, Auteur ; Kelsey FRAHLICH, Auteur ; Kopika KUHATHAAS, Auteur ; Christopher E. HART, Auteur ; Nadia BAHI-BUISSON, Auteur ; Heather E. OLSON, Auteur ; Eric D. MARSH, Auteur ; Gai AYALON, Auteur |
| Langues : |
Anglais (eng) |
| Mots-clés : |
Clinical trial readiness FOXG1 syndrome Genotype-phenotype correlations Natural history studies Neurodevelopmental disorders Rare disorders Real-world data Real-world evidence guardians of study participants provided broad consent to share de-identified data for research. This study received determinations of exemption through a central institutional review board via exemption categories 2, 7, and 8 of the revised Common Rule. Consent for publication: Not applicable. Competing interests: Elise Brimble, Elizabeth Blomenberg, and Kelsey Frahlich are current employees of Citizen Health with vested and unvested stock options. Kopika Kuhathaas and Gai Ayalon are current employees of FOXG1 Research Foundation. |
| Index. décimale : |
PER Périodiques |
| Résumé : |
BACKGROUND: FOXG1 syndrome is a severe genetic neurodevelopmental disorder characterized by intellectual and developmental disabilities (IDD), postnatal microcephaly, epilepsy, and movement disorder. With the advent of molecular therapies, establishing the natural history of FOXG1 syndrome is critical to enable clinical trial readiness. However, traditional study designs are challenging to implement for rare disorders without significant burden to participants. METHODS: The study population included 101 children and adults with (likely) pathogenic variants in or involving FOXG1 (ages 0.4 - 34.8 years). Participant medical records underwent systematic annotation and harmonization of recorded clinical phenotypes, interventions, and outcomes through use of a patient-centric real-world data (RWD) platform. Retrospective medical record data were paired with prospective administration of validated measures of development and behavior, including the Vineland-3, the Aberrant Behavior Checklist, and the Children’s Sleep Habits Questionnaire. Descriptive and inferential statistics were employed to characterize longitudinal phenotypes and to explore genotype-phenotype correlations. RESULTS: Through systematic evaluation of 101 people with FOXG1 syndrome, we generated a robust dataset encompassing >40,000 annotated clinical terminology concepts that represent >770 cumulative patient data years. Core clinical phenotypes include IDD, gastrointestinal disorders, strabismus, epilepsy, movement disorders, and sleep problems. The FOXG1 syndrome behavioral phenotype is characterized by irritability, including aggressive behaviors, stereotypies, social withdrawal, and lethargy; in those with missense variants, features of autism spectrum disorders are also reported. Data derived from both medical records and validated measures confirm and expand upon previously described genotype-phenotype correlations, whereby truncating variants are associated with greater limitations across motor and communication domains, as well as increased frequency of core FOXG1 syndrome phenotypes. Further, individuals with truncating variants had higher scores on a composite measure of FOXG1 syndrome severity, which persists when modeled longitudinally. Employing the same composite measure, we demonstrate that FOXG1 syndrome is a static encephalopathy without evidence of neurodegeneration. CONCLUSIONS: By combining retrospective RWD with prospective survey administration in a large sample population, we establish the natural history of FOXG1 syndrome and highlight candidate clinical endpoints for use in clinical trials, including quantitative evaluations of communication and movement disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-025-09653-1. |
| En ligne : |
https://dx.doi.org/10.1186/s11689-025-09653-1 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 |
in Journal of Neurodevelopmental Disorders > 17 (2025)
[article] Longitudinal characterization of clinical, developmental, and behavioral phenotypes in 101 children and adults with FOXG1 syndrome [texte imprimé] / Elise BRIMBLE, Auteur ; Pam VENTOLA, Auteur ; Elizabeth BLOMENBERG, Auteur ; Kelsey FRAHLICH, Auteur ; Kopika KUHATHAAS, Auteur ; Christopher E. HART, Auteur ; Nadia BAHI-BUISSON, Auteur ; Heather E. OLSON, Auteur ; Eric D. MARSH, Auteur ; Gai AYALON, Auteur. Langues : Anglais ( eng) in Journal of Neurodevelopmental Disorders > 17 (2025)
| Mots-clés : |
Clinical trial readiness FOXG1 syndrome Genotype-phenotype correlations Natural history studies Neurodevelopmental disorders Rare disorders Real-world data Real-world evidence guardians of study participants provided broad consent to share de-identified data for research. This study received determinations of exemption through a central institutional review board via exemption categories 2, 7, and 8 of the revised Common Rule. Consent for publication: Not applicable. Competing interests: Elise Brimble, Elizabeth Blomenberg, and Kelsey Frahlich are current employees of Citizen Health with vested and unvested stock options. Kopika Kuhathaas and Gai Ayalon are current employees of FOXG1 Research Foundation. |
| Index. décimale : |
PER Périodiques |
| Résumé : |
BACKGROUND: FOXG1 syndrome is a severe genetic neurodevelopmental disorder characterized by intellectual and developmental disabilities (IDD), postnatal microcephaly, epilepsy, and movement disorder. With the advent of molecular therapies, establishing the natural history of FOXG1 syndrome is critical to enable clinical trial readiness. However, traditional study designs are challenging to implement for rare disorders without significant burden to participants. METHODS: The study population included 101 children and adults with (likely) pathogenic variants in or involving FOXG1 (ages 0.4 - 34.8 years). Participant medical records underwent systematic annotation and harmonization of recorded clinical phenotypes, interventions, and outcomes through use of a patient-centric real-world data (RWD) platform. Retrospective medical record data were paired with prospective administration of validated measures of development and behavior, including the Vineland-3, the Aberrant Behavior Checklist, and the Children’s Sleep Habits Questionnaire. Descriptive and inferential statistics were employed to characterize longitudinal phenotypes and to explore genotype-phenotype correlations. RESULTS: Through systematic evaluation of 101 people with FOXG1 syndrome, we generated a robust dataset encompassing >40,000 annotated clinical terminology concepts that represent >770 cumulative patient data years. Core clinical phenotypes include IDD, gastrointestinal disorders, strabismus, epilepsy, movement disorders, and sleep problems. The FOXG1 syndrome behavioral phenotype is characterized by irritability, including aggressive behaviors, stereotypies, social withdrawal, and lethargy; in those with missense variants, features of autism spectrum disorders are also reported. Data derived from both medical records and validated measures confirm and expand upon previously described genotype-phenotype correlations, whereby truncating variants are associated with greater limitations across motor and communication domains, as well as increased frequency of core FOXG1 syndrome phenotypes. Further, individuals with truncating variants had higher scores on a composite measure of FOXG1 syndrome severity, which persists when modeled longitudinally. Employing the same composite measure, we demonstrate that FOXG1 syndrome is a static encephalopathy without evidence of neurodegeneration. CONCLUSIONS: By combining retrospective RWD with prospective survey administration in a large sample population, we establish the natural history of FOXG1 syndrome and highlight candidate clinical endpoints for use in clinical trials, including quantitative evaluations of communication and movement disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11689-025-09653-1. |
| En ligne : |
https://dx.doi.org/10.1186/s11689-025-09653-1 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 |
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