A recent study has reported on three classes of mutations within the gene SATB1 which result in three variations of a neurodevelopmental disorder.
SATB1 specifically encodes a dimeric/tetrameric transcription factor which is crucial in development and maturation of T cells. A recent study found significant statistical enrichment of de novo variants within this gene in two large neurodevelopment disorder cohorts. This study suggested a potential contribution of SATB1 in brain development.
In a new study, published in The American Journal of Human Genetics, an international team from 12 countries identified 42 patients with rare (likely) pathogenic variants in SATB1. The team found that these patients were all displaying a range of similar symptoms, albeit of varying severity. Overall, they observed a broad phenotypic spectrum, characterised by neurodevelopmental delay, intellectual disability, muscle tone abnormalities, spasticity, epilepsy, behaviour problems, facial dysmorphisms and dental abnormalities.
Variants within SATB1 were found to have different effects on the cell. For example, missense variants in the CUT1 and CUT2 DNA-binding domains resulted in a more severe phenotype, whereas variants predicted to result in haploinsufficiency were associated with a milder clinical presentation.
The team found that the mutations belonged to three different classes. The first class caused loss-of-function of the SATB1 gene and halved the production of the encoded protein. This resulted in less severe syndrome. The second class contained four mutations which encoded shorter proteins. These proteins were less efficient and thus resulted in an intermediary syndrome. The third class encompassed variants that modified the encoded protein, making it more active. This caused the protein to bind better to DNA and thus diminished the expression of genes it regulated. This class resulted in more severe disease.
This study emphasises that in-depth mutation-specific genotype-phenotype studies are important to fully capture disease complexity and to explain phenotypic variability.
Dr Alexandre Reymond, Director of the Center for Integrative Genomics at the University of Lausanne in Switzerland stated:
“These results demonstrate that each mutation is different and that is essential to understand their mode of action in order to explain the origin of genetic diseases.
We must go beyond sequencing, which is only a first step.”
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