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. 2023 Jul 12:17:1219262.
doi: 10.3389/fnins.2023.1219262. eCollection 2023.

Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

Benedetta Kassabian  1   2 , Christina Dühring Fenger  1   3 , Marjolaine Willems  4 , Angel Aledo-Serrano  5 , Tarja Linnankivi  6 , Pamela Pojomovsky McDonnell  7   8   9 , Laina Lusk  9 , Birgit Susanne Jepsen  10 , Michael Bayat  11 , Anja Kattentidt  12 , Anna Abulí Vidal  13 , Gabriel Valero-Lopez  14 , Helena Alarcon-Martinez  15 , Kimberly Goodspeed  16   17 , Marjon van Slegtenhorst  18 , Tahsin Stefan Barakat  18   19   20 , Rikke S Møller  1   21 , Katrine M Johannesen  1   22 , Guido Rubboli  1   23
Affiliations

Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

Benedetta Kassabian et al. Front Neurosci. .

Erratum in

  • Corrigendum: Intrafamilial variability in SLC6A1-related neurodevelopmental disorders.
    Kassabian B, Fenger CD, Willems M, Aledo-Serrano A, Linnankivi T, McDonnell PP, Lusk L, Jepsen BS, Bayat M, Kattentidt-Mouravieva AA, Vidal AA, Valero-Lopez G, Alarcon-Martinez H, Goodspeed K, van Slegtenhorst M, Barakat TS, Møller RS, Johannesen KM, Rubboli G. Kassabian B, et al. Front Neurosci. 2023 Aug 11;17:1270299. doi: 10.3389/fnins.2023.1270299. eCollection 2023. Front Neurosci. 2023. PMID: 37638311 Free PMC article.

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.

Keywords: SLC6A1; epilepsy; intellectual disability; intrafamilial variability; neurodevelopmental disorders.

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Conflict of interest statement

KG has consulted for Taysha Gene Therapy, Jaguar Gene Therapy, Astellas Gene Therapy, and all Stripes for unrelated work. She also serves as co-chair of the Clinical Advisory Board (unpaid) for the non-profit COMBINEDBrain, which involves collaborations on SLC6A1-NDD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
EEG tracings of the twins sisters (II.1 and II.2) of Family J, at the age of 3 years, showing in both subjects burst of hypersynchronous delta activities during wakefulness.
Figure 2
Figure 2
(A) Pedigrees of the 12 families reported in this study and main clinical features in the reported families. (B) Bar graph illustrating the prevalence of the neurological features in the probands and first/second degree relatives.
Figure 3
Figure 3
The 12 SLC6A1-variants displayed on GAT-1.
See this image and copyright information in PMC

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