Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy

Abstract

Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic‐dyskinetic encephalopathy

“…24 Patients PI4KA variants on protein level from three previously published studies. [6][7][8] Bi-allelic PI4K2A variants on protein level from one previously published study and our study. 9 Missense/indel variants are found above protein illustrations, frameshift/stop variants below protein illustrations.…”

“…Recent studies described 22 affected individuals with bi-allelic variants in the phosphatidylinositol 4-kinase alpha gene (PI4KA, OMIM *600286) causing a spectrum of neurodevelopmental disorder (NDD), brain malformations, contractures, hypomyelinating leukodystrophy, inflammatory bowel disease (IBD), and primary immunodeficiency (PID). [6][7][8] To this date, only two homozygous variants in the phosphatidylinositol 4-kinase type 2 alpha gene (PI4K2A) were reported to be associated with NDD phenotypes. 9,10 The first and most striking report showed homozygous nonsense variants in PI4K2A in two affected siblings presenting with NDD, epilepsy, myoclonus, and akathisia.…”

“…Recent studies described 22 affected individuals with bi‐allelic variants in the phosphatidylinositol 4‐kinase alpha gene ( PI4KA , OMIM *600286) causing a spectrum of neurodevelopmental disorder (NDD), brain malformations, contractures, hypomyelinating leukodystrophy, inflammatory bowel disease (IBD), and primary immunodeficiency (PID). 6 , 7 , 8 …”

Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization

“…The minigene assays were instrumental to confirm the pathogenic role of an intronic variant in MLC1 (c.597 + 37C > G), a gene not expressed in PBMC or fibroblasts, and another intronic variant in EIF2B5 (c.1156 + 13 G > A), which led to a mild form of ovarioleukodystrophy. 26 We also performed targeted lipidomics, which proved a pathogenic role for variants in genes related to lipid metabolism such as ACER3 , DEGS1 , 21 and PI4KA , 22 together with qRT-PCR, Western blots, or immunofluorescence as required (eTable 5, links.lww.com/WNL/B741 ). In other cases that were not amenable to experimental validation (5 remaining until 91), we reported out VUS highly compatible with the clinical and MRI picture and segregation and were considered solved by expert assessment.…”

“…with leukodystrophy and identified in patients LNF-107 and VH-3 22,34 (Figure 4C), (3) the mitochondrial ribosomeassociated GTPase 1 (MTG1) that plays a role in the regulation of mitochondrial ribosome assembly and translational activity (Figure 4D), and (4) the potassium voltage-gated channel subfamily A regulatory beta subunit 2 protein (KCNAB2) (Figure 4E). While Genematcher was key to find additional cases for DEGS1 and PI4KA deficiencies, matches for putative candidates such as MTG1 and KCNAB2 are yet to be found.…”