Delineating biallelic PI4KA variants as a cause of a complex neurological, gastrointestinal and immunological syndromic disorder

Salter, Claire (2025) Delineating biallelic PI4KA variants as a cause of a complex neurological, gastrointestinal and immunological syndromic disorder. University of Exeter, Doctoral Thesis, 334pp.

Record type: Thesis (Doctoral)

Abstract

This thesis documents clinical, genomic and functional studies of a novel, highly variable and mechanistically complex syndrome associated with biallelic PI4KA variants (PI4KA-related disorder), which encodes phosphatidylinositol 4-kinase alpha (PI4KIIIa), a protein central to multiple cellular signalling pathways and the maintenance of cell polarity, actin dynamics and plasma membrane identity.

Chapter three describes the discovery of PI4KA-related disorder. This finding, stemming from investigations in an extended Amish pedigree with a distinct, severe neonatally lethal multiple intestinal atresia (MIA), entailed clinical and molecular studies. Nine additional affected individuals from seven unrelated families were subsequently identified with phenotypes ranging from a severe antenatal neurodevelopmental presentation to a complex neurodevelopmental disorder of varying severity with/without an associated immunodeficiency and/or gastrointestinal symptomatology. These clinical presentations exhibit significant overlap to disorders associated with biallelic variants in PI4KIIIα’s molecular binding partners; TTC7A-related gastrointestinal defects and immunodeficiency syndrome, and HYCC1-related hypomyelinating leukodystrophy 5. Protein modelling and in vitro functional studies presented in this chapter identify a likely pathomechanism for the extensive clinical variability.

Chapter four documents studies that further delineate the phenotypic spectrum and genetic basis of PI4KA-related disorder in 44 affected individuals, and enable development of clinical management guidelines. Four overlapping clinical subtypes that are characteristic of the condition were identified, with onset ranging from foetal to adult life. Protein modelling studies show utility in variant classification when combined with detailed clinical phenotyping. Whilst genotype-phenotype correlations cannot be comprehensively ascribed due to the inherent molecular complexities of PI4KIIIa function, correlations were identified associated with both gastrointestinal and neurological presentations.

Chapter five describes data from collaborative studies of the immunological aspects of PI4KA-related disorder. These define B-cell anomalies, with failure of B-cell differentiation, as the predominate immunopathology alongside treatment options that may improve morbidity and mortality. This chapter also documents the development of the PI4KA-Community support group, website and establishment of a patient registry in partnership with parents of a child with the condition. In combination, these will enable ongoing investigations into the natural history of this rare disorder and dissemination of translational research findings.

Together these studies provide important new scientific and clinical insights into the complex pathomolecular basis and diverse phenotypic spectrum of PI4KA-related disorder. In turn this facilitates improved diagnostic provision and provides an exceptional opportunity to develop therapeutic interventions, ultimately improving healthcare outcomes.

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