Abstract
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.
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.
| Original language | English |
|---|---|
| Article number | 1219262 |
| Pages (from-to) | 01-11 |
| Number of pages | 11 |
| Journal | Frontiers in Neuroscience |
| Volume | 17 |
| DOIs | |
| Publication status | Published - 12 Jul 2023 |
Bibliographical note
Funding Information:We thank the families for their collaboration. We thank the SLC6A1 Connect for invaluable support and collaboration.
Publisher Copyright:
Copyright © 2023 Kassabian, Fenger, Willems, Aledo-Serrano, Linnankivi, McDonnell, Lusk, Jepsen, Bayat, Kattentidt, Vidal, Valero-Lopez, Alarcon-Martinez, Goodspeed, van Slegtenhorst, Barakat, Møller, Johannesen and Rubboli.