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Expanding the Phenotype: A Novel Case of VPS45 Deficiency with HLH and Progressive Neurological Involvement

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction
VPS45 deficiency is a rare autosomal recessive disorder caused by mutations in the VPS45 gene, which encodes a protein essential for intracellular vesicular trafficking. The condition primarily presents with neutropenia, recurrent infections, hepatosplenomegaly, cytopenias and bone marrow fibrosis. Neurodevelopmental abnormalities such as global developmental delay, intellectual disability, hypotonia, seizures and cortical blindness have been reported previously. Additional features may include speech delay, ataxia, feeding difficulties, and, in some cases, sensorineural hearing loss and retinal abnormalities. As less than 40 patients have been described worldwide the phenotype is still evolving. Here we present a case with progressive neurological symptoms.

Case Presentation
We present a 15-year-old female with a complex clinical history, who was diagnosed with familial hemophagocytic lymphohistiocytosis (HLH) in infancy, leading to bone marrow transplant at age 4 months. Neurologically, she developed nystagmus at 6 months of age, followed by global developmental delay, ADHD and abnormal movements suggestive of chorea, which have remained stable. Brain imaging showed calcifications in the basal ganglia and subcortical white matter of the frontal lobes. She has gait ataxia and fine motor difficulties, including dysgraphia. Additionally, she has short stature, facial dysmorphism, atypical dentition, primary ovarian insufficiency, history of multiple fractures, atypical bony development in feet, and hypercholesterolemia. Her family history is notable for a brother who died in infancy from HLH and two healthy siblings.

Diagnostic Workup
The patient underwent extensive genetic testing, including whole genome sequencing, mitochondrial DNA sequencing, chromosomal microarray, STXBP2 mutation analysis, Correlagen ZAP70 DNA sequencing test which were all taken from pre-bone marrow transplant DNA and all were negative. Whole genome sequencing was also performed from skin fibroblasts and was negative. However, a research reanalysis of genomic data revealed novel biallelic missense VPS45 variants, c.652C>T and c.1157G>A, in the proband which were also confirmed by Sanger sequencing. Parental testing demonstrated that the variants were inherited in trans from unaffected carrier parents. Additionally, the same variants were also seen in the whole exome data of the affected deceased brother.

Discussion
VPS45 deficiency was first described in 2013, with 14 patients showing early-onset systemic symptoms, including fevers, nephromegaly, neutropenia, and progressive anemia, as well as neurological phenotypes like autism. By 2024, an additional 18 patients had been reported, with expanded phenotypes including bilateral hip subluxation, blindness, periventricular gliosis, conductive hearing loss, myelofibrosis, dental issues, microcephaly, and nystagmus. A specific VPS45 variant (E238K) has been identified in all patients with neurological symptoms, though

this variant was not present in our case. Our proband's neurological phenotype is more pronounced than previously described, raising the possibility of a phenotype expansion. The patient’s bone marrow transplant and subsequent neurological progression are consistent with previously reported cases, where bone marrow transplantation was required as part of the treatment.

Conclusion
This case adds to the expanding phenotypic spectrum of biallelic VPS45 deficiency and underscores the neurological involvement in the condition, which appears to be more striking in our proband than in previously described cases. The presentation in this family, particularly in the context of HLH, highlights the need for clinicians to consider VPS45 deficiency as a diagnostic possibility when evaluating similar cases. This case also serves as an important reference for genetic counseling and future diagnostic approaches in complex neurogenetic disorders.

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