Identifying novel heterozygous PI4KA variants in fetal abnormalities

Area of Science:

• Genetics
• Molecular Biology
• Fetal Medicine

Background:

• PI4KA-related disorders present with variable symptoms including neurological issues, gastrointestinal problems, and immunodeficiency.
• Prenatal detection of PI4KA variants is crucial for understanding fetal development impacts.

Purpose of the Study:

• To identify and characterize novel PI4KA variants detected during prenatal screening.
• To evaluate the functional impact of these variants on fetal development and PI4KA enzyme activity.

Main Methods:

• Fetal ultrasound and MRI for imaging.
• Whole exome sequencing (WES) for variant detection, validated by Sanger sequencing.
• Bioinformatics, minigene splicing assays, and enzyme activity assays for functional analysis.

Main Results:

• Prenatal ultrasound and MRI revealed fetal intestinal obstruction.
• Compound heterozygous PI4KA variants (c.2802_2863-40del and c.2819C>T [p.Ala940Val]) were identified.
• The c.2802_2863-40del variant altered mRNA splicing, while c.2819C>T significantly reduced PI4KA enzyme activity.

Conclusions:

• The study expands the known spectrum of PI4KA mutations.
• Identified PI4KA variants impact RNA splicing and enzyme function, contributing to fetal abnormalities.
• Findings offer guidance for prenatal genetic counseling regarding PI4KA-related disorders.