Bi-allelic variants in the ASTN1 gene have been linked to a range of neurodevelopmental disorders, according to a study published in The American Journal of Human Genetics.
The ASTN1 gene encodes astrotactin 1, a protein involved in neuronal migration during brain development. This process allows neurons to move to their correct positions in the developing brain, which is essential for normal formation of structures such as the cerebral cortex and cerebellum. Disruption of this process can lead to structural brain abnormalities and developmental impairment.
In the study, researchers identified 18 individuals from 12 unrelated families who carried ultra-rare, likely damaging variants affecting both copies of ASTN1. Most affected individuals had developmental delay or intellectual disability, ranging from mild to severe. Additional clinical features included autism spectrum disorder, attention-deficit/hyperactivity disorder, epilepsy, low muscle tone, movement abnormalities, and dysmorphic facial features.
Brain imaging findings were variable. Some individuals had normal magnetic resonance imaging results, while others showed abnormalities such as a thin corpus callosum, cerebellar changes, polymicrogyria, or lissencephaly. This variability suggests that ASTN1-related disorders may present with a broad clinical spectrum.
The study also identified different genetic patterns within the cohort. Most individuals had recessive, bi-allelic variants in ASTN1. One individual carried heterozygous variants in both ASTN1 and ASTN2, a related gene involved in neuronal migration, suggesting a possible combined genetic effect. In some cases, multilocus pathogenic variation was observed, meaning that more than one gene contributed to the phenotype.
These findings highlight the importance of comprehensive genomic testing in patients with unexplained neurodevelopmental disorders. Exome or genome sequencing may identify rare bi-allelic variants that could be missed by more limited testing panels. The study also emphasizes the need to consider complex inheritance patterns, including potential contributions from more than one gene.
Recognition of ASTN1 as a gene associated with neurodevelopmental disorders may support more accurate diagnosis, improved genetic counseling, and better-informed family risk assessment as genomic testing becomes more widely used in pediatric and neurological practice.
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