GABRA1-Related Disorders: From Genetic to Functional Pathways

Elisa Musto^#^{1

2

3}, Vivian W Y Liao^#⁴, Katrine M Johannesen^{1

5}, Christina D Fenger^{1

6}, Damien Lederer⁷, Kavitha Kothur⁸, Katrina Fisk⁹, Bruce Bennetts^{9

10}, Pascal Vrielynck¹¹, Delphine Delaby¹¹, Berten Ceulemans¹², Sarah Weckhuysen^{13

14

15}, Peter Sparber¹⁶, Arjan Bouman¹⁷, Simone Ardern-Holmes^{8

18}, Christopher Troedson¹⁸, Domenica I Battaglia², Himanshu Goel¹⁹, Timothy Feyma²⁰, Somayeh Bakhtiari^{21

22}, Linda Tjoa²³, Martin Boxill²⁴, Nina Demina¹⁶, Olga Shchagina¹⁶, Elena Dadali¹⁶, Michael Kruer^{21

22}, Gaetano Cantalupo^{25

26

27}, Ilaria Contaldo², Tilman Polster²⁸, Bertrand Isidor²⁹, Stefania M Bova³⁰, Walid Fazeli³¹, Leen Wouters³², Maria J Miranda³³, Francesca Darra^{25

26

27}, Elisa Pede², Diana Le Duc³⁴, Rami Abou Jamra³⁴, Sébastien Küry^{35

36}, Jacopo Proietti^{25

37}, Niamh McSweeney³⁸, Elly Brokamp³⁹, Peter Ian Andrews⁴⁰, Marie Gouray Garcia⁴¹, Mary Chebib⁴, Rikke S Møller^#^{1

42}, Philip K Ahring⁴, Elena Gardella^#^{1

42}

Affiliations

¹ Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark.
² Pediatric Neurology, Department of Woman and Child Health and Public Health, Child Health Area, Catholic University UCSC, Rome, Italy.
³ Epilepsy and Movement Disorder Neurology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
⁴ Brain and Mind Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁵ Department of Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
⁶ Amplexa Genetics, Odense, Denmark.
⁷ Center for Human Genetics, Institut de Pathologie et de Génétique, Gosselies, Belgium.
⁸ Kids Neuroscience Centre, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
⁹ Sydney Genome Diagnostics, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹⁰ Specialty of Genomic Medicine, Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹¹ Reference Center for Refractory Epilepsy, Catholic University of Louvain, William Lennox Neurological Hospital, Ottignies, Belgium.
¹² Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
¹³ Applied & Translational Neurogenomics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
¹⁴ Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
¹⁵ Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
¹⁶ Research Center for Medical Genetics Moskvorechie 1, Moscow, Russia.
¹⁷ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
¹⁸ T. Y. Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁹ Hunter Genetics, Newcastle, New South Wales, Australia.
²⁰ Gillette Children's Specialty Healthcare, Saint Paul, MN, USA.
²¹ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
²² Departments of Child Health, Neurology, and Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ, USA.
²³ Townsville University Hospital, Douglas, Queensland, Australia.
²⁴ Department of Pediatrics, Viborg Regional Hospital, Viborg, Denmark.
²⁵ Child Neuropsychiatry Section, Department of Surgical Sciences, Dentistry, Gynecology and Paediatrics, University of Verona, Verona, Italy.
²⁶ UOC Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria Integrata (full member of the ERN EpiCare), Verona, Italy.
²⁷ Center for Research on Epilepsies in Pediatric age (CREP), Verona, Italy.
²⁸ Department of Epileptology (Krankenhaus Mara), Bielefeld University Medical School, Bielefeld, Germany.
²⁹ CHU Nantes, Service de Génétique Médicale, Nantes, France.
³⁰ Pediatric Neurology Unit, V. Buzzi Children's Hospital, Milan, Italy.
³¹ Department of Neuropediatrics, Children's Hospital, University of Bonn, Bonn, Germany.
³² Department of Pediatrics, Ziekenhuis Oost-Limburg, Genk, Belgium.
³³ Department of Pediatrics, Pediatric Neurology, Herlev University Hospital, Copenhagen University, Herlev, Denmark.
³⁴ Department of Human Genetics, University of Leipzig Faculty of Medicine, Leipzig, Germany.
³⁵ Service de Génétique Médicale, CHU Nantes, Nantes, France.
³⁶ l'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
³⁷ Irish Centre for Fetal and Neonatal Translational Research, Child Neuropsychiatry, Cork, Ireland.
³⁸ Department of Paediatrics, Cork University Hospital, Cork, Ireland.
³⁹ Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁰ Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
⁴¹ Centre Hospitalier de Cholet, Cholet, France.
⁴² Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

^# Contributed equally.

PMID: 37606373
DOI: 10.1002/ana.26774

GABRA1-Related Disorders: From Genetic to Functional Pathways

Elisa Musto et al. Ann Neurol. 2023.

. 2023 Aug 22.

doi: 10.1002/ana.26774. Online ahead of print.

Authors

Affiliations

¹ Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark.
² Pediatric Neurology, Department of Woman and Child Health and Public Health, Child Health Area, Catholic University UCSC, Rome, Italy.
³ Epilepsy and Movement Disorder Neurology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
⁴ Brain and Mind Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁵ Department of Genetics, University Hospital of Copenhagen, Copenhagen, Denmark.
⁶ Amplexa Genetics, Odense, Denmark.
⁷ Center for Human Genetics, Institut de Pathologie et de Génétique, Gosselies, Belgium.
⁸ Kids Neuroscience Centre, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia.
⁹ Sydney Genome Diagnostics, Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
¹⁰ Specialty of Genomic Medicine, Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹¹ Reference Center for Refractory Epilepsy, Catholic University of Louvain, William Lennox Neurological Hospital, Ottignies, Belgium.
¹² Department of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
¹³ Applied & Translational Neurogenomics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
¹⁴ Department of Neurology, Antwerp University Hospital, Antwerp, Belgium.
¹⁵ Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
¹⁶ Research Center for Medical Genetics Moskvorechie 1, Moscow, Russia.
¹⁷ Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
¹⁸ T. Y. Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁹ Hunter Genetics, Newcastle, New South Wales, Australia.
²⁰ Gillette Children's Specialty Healthcare, Saint Paul, MN, USA.
²¹ Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
²² Departments of Child Health, Neurology, and Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, AZ, USA.
²³ Townsville University Hospital, Douglas, Queensland, Australia.
²⁴ Department of Pediatrics, Viborg Regional Hospital, Viborg, Denmark.
²⁵ Child Neuropsychiatry Section, Department of Surgical Sciences, Dentistry, Gynecology and Paediatrics, University of Verona, Verona, Italy.
²⁶ UOC Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria Integrata (full member of the ERN EpiCare), Verona, Italy.
²⁷ Center for Research on Epilepsies in Pediatric age (CREP), Verona, Italy.
²⁸ Department of Epileptology (Krankenhaus Mara), Bielefeld University Medical School, Bielefeld, Germany.
²⁹ CHU Nantes, Service de Génétique Médicale, Nantes, France.
³⁰ Pediatric Neurology Unit, V. Buzzi Children's Hospital, Milan, Italy.
³¹ Department of Neuropediatrics, Children's Hospital, University of Bonn, Bonn, Germany.
³² Department of Pediatrics, Ziekenhuis Oost-Limburg, Genk, Belgium.
³³ Department of Pediatrics, Pediatric Neurology, Herlev University Hospital, Copenhagen University, Herlev, Denmark.
³⁴ Department of Human Genetics, University of Leipzig Faculty of Medicine, Leipzig, Germany.
³⁵ Service de Génétique Médicale, CHU Nantes, Nantes, France.
³⁶ l'Institut du Thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
³⁷ Irish Centre for Fetal and Neonatal Translational Research, Child Neuropsychiatry, Cork, Ireland.
³⁸ Department of Paediatrics, Cork University Hospital, Cork, Ireland.
³⁹ Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴⁰ Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
⁴¹ Centre Hospitalier de Cholet, Cholet, France.
⁴² Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.

^# Contributed equally.

PMID: 37606373
DOI: 10.1002/ana.26774

Abstract

Objective: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations.

Methods: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants.

Results: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy.

Interpretation: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.

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References

1. Masiulis S, Desai R, Uchański T, et al. GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature 2019;565:454-459.
1. Pettersen EF, Goddard TD, Huang CC, et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci 2021;30:70-82.
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GABRA1-Related Disorders: From Genetic to Functional Pathways

Affiliations

GABRA1-Related Disorders: From Genetic to Functional Pathways

Authors

Affiliations

Abstract

References

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