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Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

INTRODUCTION: Phenotypic 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 hypotoni...

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Autores principales: Kassabian, Benedetta, Fenger, Christina Dühring, Willems, Marjolaine, Aledo-Serrano, Angel, Linnankivi, Tarja, McDonnell, Pamela Pojomovsky, Lusk, Laina, Jepsen, Birgit Susanne, Bayat, Michael, Kattentidt-Mouravieva, Anja A., Vidal, Anna Abulí, Valero-Lopez, Gabriel, Alarcon-Martinez, Helena, Goodspeed, Kimberly, van Slegtenhorst, Marjon, Barakat, Tahsin Stefan, Møller, Rikke S., Johannesen, Katrine M., Rubboli, Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368872/
https://www.ncbi.nlm.nih.gov/pubmed/37502687
http://dx.doi.org/10.3389/fnins.2023.1219262
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author Kassabian, Benedetta
Fenger, Christina Dühring
Willems, Marjolaine
Aledo-Serrano, Angel
Linnankivi, Tarja
McDonnell, Pamela Pojomovsky
Lusk, Laina
Jepsen, Birgit Susanne
Bayat, Michael
Kattentidt-Mouravieva, Anja A.
Vidal, Anna Abulí
Valero-Lopez, Gabriel
Alarcon-Martinez, Helena
Goodspeed, Kimberly
van Slegtenhorst, Marjon
Barakat, Tahsin Stefan
Møller, Rikke S.
Johannesen, Katrine M.
Rubboli, Guido
author_facet Kassabian, Benedetta
Fenger, Christina Dühring
Willems, Marjolaine
Aledo-Serrano, Angel
Linnankivi, Tarja
McDonnell, Pamela Pojomovsky
Lusk, Laina
Jepsen, Birgit Susanne
Bayat, Michael
Kattentidt-Mouravieva, Anja A.
Vidal, Anna Abulí
Valero-Lopez, Gabriel
Alarcon-Martinez, Helena
Goodspeed, Kimberly
van Slegtenhorst, Marjon
Barakat, Tahsin Stefan
Møller, Rikke S.
Johannesen, Katrine M.
Rubboli, Guido
author_sort Kassabian, Benedetta
collection PubMed
description INTRODUCTION: Phenotypic 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. METHODS: We 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. RESULTS: Main 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. DISCUSSION: Our 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.
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spelling pubmed-103688722023-07-27 Intrafamilial variability in SLC6A1-related neurodevelopmental disorders Kassabian, Benedetta Fenger, Christina Dühring Willems, Marjolaine Aledo-Serrano, Angel Linnankivi, Tarja McDonnell, Pamela Pojomovsky Lusk, Laina Jepsen, Birgit Susanne Bayat, Michael Kattentidt-Mouravieva, Anja A. Vidal, Anna Abulí Valero-Lopez, Gabriel Alarcon-Martinez, Helena Goodspeed, Kimberly van Slegtenhorst, Marjon Barakat, Tahsin Stefan Møller, Rikke S. Johannesen, Katrine M. Rubboli, Guido Front Neurosci Neuroscience INTRODUCTION: Phenotypic 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. METHODS: We 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. RESULTS: Main 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. DISCUSSION: Our 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. Frontiers Media S.A. 2023-07-12 /pmc/articles/PMC10368872/ /pubmed/37502687 http://dx.doi.org/10.3389/fnins.2023.1219262 Text en 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. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Kassabian, Benedetta
Fenger, Christina Dühring
Willems, Marjolaine
Aledo-Serrano, Angel
Linnankivi, Tarja
McDonnell, Pamela Pojomovsky
Lusk, Laina
Jepsen, Birgit Susanne
Bayat, Michael
Kattentidt-Mouravieva, Anja A.
Vidal, Anna Abulí
Valero-Lopez, Gabriel
Alarcon-Martinez, Helena
Goodspeed, Kimberly
van Slegtenhorst, Marjon
Barakat, Tahsin Stefan
Møller, Rikke S.
Johannesen, Katrine M.
Rubboli, Guido
Intrafamilial variability in SLC6A1-related neurodevelopmental disorders
title Intrafamilial variability in SLC6A1-related neurodevelopmental disorders
title_full Intrafamilial variability in SLC6A1-related neurodevelopmental disorders
title_fullStr Intrafamilial variability in SLC6A1-related neurodevelopmental disorders
title_full_unstemmed Intrafamilial variability in SLC6A1-related neurodevelopmental disorders
title_short Intrafamilial variability in SLC6A1-related neurodevelopmental disorders
title_sort intrafamilial variability in slc6a1-related neurodevelopmental disorders
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10368872/
https://www.ncbi.nlm.nih.gov/pubmed/37502687
http://dx.doi.org/10.3389/fnins.2023.1219262
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