EP07.12: Novel PI4KA variants causing fetal abnormalities

The clinical manifestations of PI4KA are highly variable, mainly characterised by neurological dysfunction, gastrointestinal manifestations, and combined immune deficiency. The objective of this study was to explore the new spectrum of PI4KA variants at the prenatal stage and the effects they have on fetal development. Systematic ultrasound screening was performed in the fetus, and antenatal and Postal MRI and autopsy were conducted. The novel variants of PI4KA were identified by the clinical Whole Exome Sequencing (WES) and Sanger sequencing. The variants were predicted with bioinformatics programs. Minigene splicing assays were used to analyse splicing effect of the variant. The wild or mutant PI4KA protein fragment was purified and enzyme activity was determined. Ultrasound, MRI and autopsy result of the fetus showed the dilated small bowel with obstruction. Compound heterozygous variants (NM_058004.3: c.2802_2863-40del and c.2819C>T) were detected by clinical trio-WES in the PI4KA of the affected fetus. Both variants were predicted deleterious. PI4KA c.2802_2863-40del produced three types of mRNA. PI4KA c.2819C>T significantly reduced the enzyme activity. This study extended the mutational spectrum of PI4KA and may provide guidance for genetic counselling. Functional experiment proved the variant caused the altering the RNA splicing and the enzyme activity.