The role of SLC6A1 in brain function
SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) are a group of conditions caused by harmful variants in the SLC6A1 gene. This gene makes the GABA (γ-aminobutyric acid) transporter 1, which helps manage inhibitory signals in the brain. When this system is disrupted it can lead to a range of problems, most often including developmental delay, epilepsy, intellectual disability, and autistic or behavioural traits. Earlier studies have described the main features of affected individuals, but less is known about how these conditions differ between family members with the same genetic variant. Understanding this variation is important, as it might explain why some people are more severely affected while their relatives show only mild symptoms.
Family patterns in SLC6A1 disorders
The investigators looked at how SLC6A1-related neurodevelopmental disorders can appear differently within the same family. They collected genetic and clinical data from 39 people across 13 families, all carrying inherited variants of the SLC6A1 gene. The team compared symptoms of probands (the first individuals in a family suspected to have genetic disease) with those of siblings and other relatives. The aim was to learn if the same mutation consistently led to the same types of symptoms, or if there was variation among family members.
The results were striking. While epilepsy and intellectual disability were seen in nearly all probands, many of their relatives with the same variant only had mild learning problems or slight behavioural traits. In some families, psychiatric symptoms were found in over half of affected members, but their severity differed between generations. These differences show why some cases may be missed and highlight the value of studying family patterns more closely.
Epilepsy, learning, and behavioural traits in focus
In this study, of the 39 people carrying SLC6A1 variants, epilepsy was the most common feature. Over 70% of probands experienced seizures which were often generalised, compared with only 36% of their siblings or other relatives. All probands showed some level of intellectual disability, mostly moderate to severe, while only around 13% of relatives had any documented cognitive impairment – usually determined through clinical assessment, not neuropsychological testing.
Behavioural or psychiatric symptoms were also quite common, occurring in more than half of all participants and in approximately 82% of probands. Neurological issues such as tremor, ataxia, or speech problems were observed in more than one-third (39%) of individuals. More details on the specific variants and features can be found in Table 1 and Figure 2 of the manuscript.
Overall, the study found 12 different SLC6A1 variants in total. Relatives showed milder problems such as learning difficulties or slightly low IQ, while probands more often had severe epilepsy and developmental delays. There was no strong link between the type of mutation and symptoms, suggesting that other genetic or environmental factors may affect how the disorder manifests. Together, these results show that SLC6A1-related disorders form a wide and varied clinical spectrum rather than one set presentation.
Not so fast
Although this study is the first to provide information on how SLC6A1-related disorders can vary within families, there are still a few limitations. Clinical data for some first- and second-degree relatives was missing or incomplete, making it harder to fully understand how symptoms differ between family members. In some cases, learning and intellectual abilities were not assessed using standard neuropsychological tests, so results may not have been completely consistent between centres. The sample size was also quite small, with only 13 families included, which limits how much the results can be generalised. Lastly, for several variants, functional studies are still lacking, so pathogenicity remains uncertain.
Why does it matter?
Understanding how SLC6A1 variants appear within families is important for both clinical care and genetic counselling. The study showed that 100% of probands had intellectual disability, while only about 13% of relatives were affected. Also, epilepsy occurred in 71% of probands compared to 36% of relatives. These differences reveal how milder or unusual cases can sometimes be missed, especially in older relatives who may not have had access to genetic testing in the past. The findings also point to the need for testing in families where a variant is already known, to allow earlier diagnosis, better counselling, and more individualised care.
Take home messages
1. SLC6A1-related disorders can vary considerably within the same family, from severe epilepsy and intellectual disability to only mild learning or behavioural problems.
2. Usually, probands are more seriously affected than their relatives, with epilepsy observed in over 70% vs 36%, and intellectual disability in 100% vs 13%.
3. Identifying this variation within families is important for accurate diagnosis and counselling, as milder cases might otherwise go unnoticed, delaying support and treatment.
Guest author: Hassan Khan, MSc
Reviewer: Barbara Fahmy, MS OTR, MPA
This article was written as part of a series of ‘journal club’ summaries for Scientific Writers Ltd and is based on the following publication.
Title: Intrafamilial variability in SLC6A1-related neurodevelopmental disorders
First Author: Kassabian B, et al.
Journal: Frontiers in Neuroscience
Date online: 12 July 2023
