Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

Frontiers in Neuroscience

Neuroscience

Marjon van Slegtenhorst¹  Tahsin Stefan Barakat²  Anna Abulí Vidal³  Christina Dühring Fenger⁴  Guido Rubboli⁵  Katrine M. Johannesen⁶  Rikke S. Møller⁷  Benedetta Kassabian⁸  Michael Bayat⁹  Tarja Linnankivi^1,10  Helena Alarcon-Martinez^1,11  Kimberly Goodspeed^1,12  Pamela Pojomovsky McDonnell^1,13  Marjolaine Willems^1,14  Laina Lusk^1,15  Angel Aledo-Serrano^1,16  Gabriel Valero-Lopez^1,17  Birgit Susanne Jepsen^1,18  Anja A. Kattentidt-Mouravieva^1,19 

[1] Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands;Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands;Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands;ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, Netherlands;Department of Clinical and Molecular Genetics, University Hospital Vall d’Hebron and Medicine Genetics Group Vall d'Hebron Research Institute (VHIR), Barcelona, Spain;Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark;Amplexa Genetics, Odense, Denmark;Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark;Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark;Department of Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark;Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark;Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark;Department of Epilepsy Genetics and Precision Medicine, Danish Epilepsy Center, Member of the European Reference Network EpiCARE, Dianalund, Denmark;Neurology Unit, Department of Neuroscience, University of Padua, Padua, Italy;Department of Neurology and Center for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark;Department of Pediatric Neurology, New Children's Hospital and Pediatric Research Center, Epilepsia Helsinki, Helsinki University Hospital and University of Helsinki, Helsinki, Finland;Department of Pediatric Neurology, Virgen de la Arrixaca University Hospital, Murcia, Spain;Department of Pediatrics, Division of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States;Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States;Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States;Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States;Epilepsy Neurogenetics Initiative, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States;Département Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHU de Montpellier Institute for Neurosciences of Montpellier, Univ Montpellier, INSERM, Montpellier, France;Epilepsy Neurogenetics Initiative, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States;Epilepsy and Neurogenetics Program—Vithas Madrid La Milagrosa University Hospital, Vithas Hospital Group, Madrid, Spain;Neurology Department, Virgen de la Arrixaca University Hospital, Murcia, Spain;Pediatric Department, Danish Epilepsy Center, Dianalund, Denmark;Stichting Zuidwester, Middelharnis, Netherlands;

关键词: SLC6A1;    intrafamilial variability;    epilepsy;    neurodevelopmental disorders;    intellectual disability;   

DOI  :  10.3389/fnins.2023.1219262

 received in 2023-05-08, accepted in 2023-06-23,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionPhenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants.MethodsWe collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers.ResultsMain clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype–phenotype associations were identified.DiscussionOur study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling.

【 授权许可】

Unknown   
Copyright © 2023 Kassabian, Fenger, Willems, Aledo-Serrano, Linnankivi, McDonnell, Lusk, Jepsen, Bayat, Kattentidt-Mouravieva, Vidal, Valero-Lopez, Alarcon-Martinez, Goodspeed, van Slegtenhorst, Barakat, Møller, Johannesen and Rubboli.