Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease

Delia Gagliardi; Charles Wade; Arianna Tucci; Henry Houlden; Jeremy Chataway; Frederik Barkhof; David S Lynch

doi:10.1136/jnnp-2024-335089

Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease

J Neurol Neurosurg Psychiatry. 2024 Dec 6:jnnp-2024-335089. doi: 10.1136/jnnp-2024-335089. Online ahead of print.

Authors

Delia Gagliardi^#¹, Charles Wade^#², Arianna Tucci³, Henry Houlden^{4

5}, Jeremy Chataway^{2

6}, Frederik Barkhof^{2

7

8}, David S Lynch^{9

5

6}

Affiliations

¹ Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
² Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK.
³ William Harvey Research Institute, Queen Mary University of London, London, UK.
⁴ Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK.
⁵ National Hospital for Neurology and Neurosurgery, London, UK.
⁶ Biomedical Research Centre, National Institute for Health Research, University College London Hospitals Foundation Trust, London, UK.
⁷ Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, London, UK.
⁸ Department of Radiology & Nuclear Medicine, Amsterdam UMC, London, UK.
⁹ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK david.lynch.13@ucl.ac.uk.

^# Contributed equally.

PMID: 39643430
DOI: 10.1136/jnnp-2024-335089

Abstract

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.

Keywords: Alexander Disease; Prevalence; UK Biobank.