Dlg4, also known as discs large MAGUK scaffold protein 4, encodes postsynaptic density protein-95 (PSD-95). PSD-95 regulates excitatory synaptic function in the brain, which is crucial for normal neural communication and brain development. It is likely involved in pathways related to neurodevelopment and synaptic plasticity [1,2].

In a study of 53 patients with DLG4 variants, most of the 45 different variants (39) were predicted to lead to loss of protein function, mainly occurring de novo. Clinical features included early-onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, indicating a brain disorder named DLG4-related synaptopathy [1].

Another study on 35 individuals with DLG4-related synaptopathy and epilepsy reported a large variety of seizure types, with focal seizures being the most common. About one-fourth had encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike-wave activation during sleep (DEE-SWAS), and all but one had neurodevelopmental delay [2].

A novel de novo heterozygous frameshift variant in a Japanese girl led to intellectual regression, autism spectrum disorder, and attention-deficit/hyperactivity disorder [3]. Dlg4 was also identified as a common candidate factor in the comorbidity of epilepsy and attention-deficit hyperactivity disorder through gene expression analysis [4].

In conclusion, Dlg4 is essential for regulating excitatory synaptic function in the brain. Studies on patients with DLG4 variants have revealed its significant role in neurodevelopmental disorders such as DLG4-related synaptopathy, which is characterized by various neurological symptoms including developmental delay, intellectual disability, and epilepsy. These findings contribute to our understanding of the mechanisms underlying these disorders and may potentially guide future diagnostic and treatment strategies.