Detection of pathogenic novel intronic splicing variants in the KIDINS220 gene causes motor developmental delay

Pathogenic variants in the KIDINS220 gene can cause SINO syndrome (OMIM #617296), VENARG syndrome (OMIM #619501), or other neurological and metabolic disorders such as obesity and nystagmus. We identified two novel intronic variants in intron 29 of KIDINS220 gene (NM_020738.4), c.4054-2A > G and c.4054-7T > C, in a female patient presenting with motor dysfunction and developmental delay. Brain MRI revealed delayed myelination. To investigate whether these intronic variants cause aberrant splicing and affect protein expression, we sequenced KIDINS220 cDNA from peripheral blood and concurrently performed a minigene splicing assay. The results indicated that KIDINS220 was not expressed in PBMCs. However, the minigene assay demonstrated that the c.4054-2A > G variant causes an in-frame 336-bp deletion in exon 30, resulting in a 112-amino acid deletion in the C-terminal region of KIDINS220 (p.(Ser1352_Ser1463del)). In contrast, the c.4054-7T > C variant did not disrupt normal splicing. Based on the patient's clinical features and functional validation of the genetic variants, our paediatricians established a diagnosis of mild motor dysfunction and developmental delay. Our findings broaden the spectrum of pathogenic variants underlying KIDINS220-related disorders and provide essential information for genetic counselling.