Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease
Rattachement africain : it, gb. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Background Alexander disease is an autosomal dominant leukodystrophy caused by heterozygous pathogenic variants in the glial fibrillar acidic protein (GFAP) gene. Although increasingly recognised, there is evidence that Alexander disease, particularly later-onset disease, is significantly underdiagnosed and its true prevalence is unknown (the only population-based prevalence was estimated at one in 2.7 million). Using the extensive UK Biobank dataset, we analysed the frequency of pathogenic and likely pathogenic variants, GFAP variants, within the UK population and identified clinical and radiological phenotypes linked to these variants. Methods Pathogenic, likely pathogenic and GFAP variants of uncertain significance were identified in the UK Biobank whole-exome sequencing data (n=4 70 000). Demographic information, previous medical history—including symptoms associated with Alexander disease—collected from self-reported data and hospital records, family history and various MRI metrics were compared between variant carriers and controls. Results We identified 36 unique pathogenic and likely pathogenic GFAP variants in 106 carriers, yielding a carrier frequency of approximately 1 in 4435. Modelling based on the UK population estimated a prevalence of 6.8 per 100 000. Carriers of pathogenic and likely pathogenic GFAP variants had higher odds of bladder dysfunction (OR 3.17, p<0.0001), upper airway dysfunction (OR 7.82, p=0.004) and psychiatric conditions (OR 1.51, p=0.04). Additionally, carriers were more likely to report a paternal history of dementia (OR 2.79, p<0.0001). MRI data revealed significant atrophy in brainstem regions among variant carriers. Conclusion Pathogenic and likely pathogenic GFAP variants are more prevalent in the general population than previously expected and are associated with clinical and radiological characteristics of Alexander disease. This study indicates that Alexander disease may be under-reported, misdiagnosed, or exhibit reduced penetrance.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease
- Date Crossref
- 06/12/2024
- Éditeur
- BMJ
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico pays non établi dans la noticeÉtablissement de santé
-
Ospedale Maggiore Neurology Unit pays non établi dans la noticeÉtablissement de santé
-
Istituti di Ricovero e Cura a Carattere Scientifico pays non établi dans la noticeÉtablissement de santé
-
National Hospital for Neurology and Neurosurgery Lysholm Department of Neuroradiology pays non établi dans la noticeÉtablissement de santé
-
UCL Queen Square Institute of Neurology Department of Neuroinflammation pays non établi dans la noticeUniversité ou école supérieure
-
University College London Biomedical Research Centre pays non établi dans la noticeUniversité ou école supérieure
-
Queen Mary University of London William Harvey Research Institute pays non établi dans la noticeUniversité ou école supérieure
-
William Harvey Research Institute pays non établi dans la noticeStructure de recherche
-
National Institute for Health and Care Research pays non établi dans la noticeOrganisme public
-
Department of Radiology & Nuclear Medicine pays non établi dans la noticeInstitution
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit — Ospedale Maggiore et Istituti di Ricovero e Cura a Carattere Scientifico, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.