SPTAN1 is located at 9q34.11, consists of 57 exons (NM_001130438.3) and encodes α-ΙΙ spectrin. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the variants at last two spectrin alter heterodimer formation between the two spectrins. The patients with severe DEE (DEE5) showed de novo in-frame variants at the last two spectrin repeats. The variants of in-frame deletion/duplication in the last two spectrin repeats led severe phenotypes due to protein aggregation with dominant negative effects. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in several patients. The truncating variants, microdeletion, or missense variants outside the α/β spectrin heterodimerization, are responsible for milder DD/ID and complex phenotypes with or without epilepsy. The recurrent p.(Arg19Trip) variant is associated with HSP and ataxia. Currently, comprehensive diagnosis of SPTAN1 variants is based on clinical symptoms and the patient’s genotype, and diagnostic genetic test is usually made through whole exome sequencing. Only in-frame variants in the last two spectrin repeats could confirm the diagnosis of DEE5.
SPTAN1