Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) present a wide range of symptoms including intellectual disability (ID), autistic spectrum disorders (ASD), and epilepsy.
• Familial phenotypic heterogeneity in SLC6A1-NDD is not well-documented, necessitating further investigation into intrafamilial variability.

Purpose of the Study:

• To investigate the intrafamilial phenotypic variability in families with pathogenic variants in the SLC6A1 gene.
• To understand the spectrum of clinical manifestations within families affected by SLC6A1-NDD.

Main Methods:

• Collected clinical, laboratory, and genetic data from 39 individuals across 13 families with inherited SLC6A1 variants.
• Data were gathered through an international network of Epilepsy and Genetic Centers.

Main Results:

• Epilepsy (71% of probands, 36% of relatives) and intellectual disability (100% of probands, 13% of relatives) were common. Psychiatric symptoms affected 51% of the cohort.
• Relatives typically exhibited milder ID and learning disabilities, contrasting with probands who had moderate to severe ID, epilepsy, and psychiatric disorders.
• No genotype-phenotype associations were identified among the 12 different SLC6A1 variants found.

Conclusions:

• Intrafamilial variability in SLC6A1-NDD is significant, with relatives often presenting milder phenotypes than probands.
• Mild cases of SLC6A1-NDD, particularly in older individuals, may be underdiagnosed due to lack of genetic testing.
• Further research into intrafamilial phenotypic variability is crucial for expanding the understanding of SLC6A1-NDD and improving genetic counseling.