Introduction
The University of Wisconsin Undiagnosed Disease Program (UW-UDP) presents a unique patient with multiple congenital anomalies and multi-system involvement associated with compound heterozygous variants in VPS50. This is the fourth reported case of VPS50-related neurodevelopmental disorder, characterized by microcephaly, seizures, and neonatal cholestasis.

 

Case Presentation
The patient was born at full-term with omphalocele, submucous cleft palate, hypospadias, and central nervous system (CNS) anomalies including dysgenesis of the corpus callosum, polymicrogyria with heterotopia, and diminutive optic nerves. His head circumference was normal at birth. He spent 123 days in the NICU for failure to thrive, requiring G-tube placement, infantile spasms, and transient neonatal cholestasis. At age 3, repeat MRI revealed progressive cerebellar atrophy. At age 10, he was nonverbal, microcephalic (Z = -3.62), and exhibited no head control. Additional findings included nystagmus, corneal opacities, hypotonia, scoliosis, hyperkinetic movements, and palmoplantar hyperkeratosis. Dysmorphic features included a wide nasal bridge, short nose, low-set ears, smooth philtrum, and overlapping toes. Medical history was also notable for retinal dystrophy, profound bilateral sensorineural hearing loss, central diabetes insipidus, mild aortic root dilation, and immunodeficiency with recurrent infections.

Family history revealed deceased fraternal twin siblings: a brother with holoprosencephaly who died shortly after birth and a sister with ventriculomegaly and partial agenesis of the corpus callosum who died at 30 days old.

 

Diagnostic Workup
The patient underwent extensive genetic testing. Early evaluations, including karyotyping, microarray, ARX gene sequencing, holoprosencephaly gene panel testing, and Stickler syndrome gene testing, were unremarkable. Clinical whole exome sequencing at age 8 identified a maternally inherited pathogenic variant in B3GLCT, a paternally inherited likely pathogenic variant in POLG, and compound heterozygous variants of uncertain significance (VUS) in GTPBP2. At age 12, whole genome sequencing by the UW-UDP identified compound heterozygous variants in VPS50: a paternally inherited splice donor variant (c.450+2T>C) and a maternally inherited 15.81 kb duplication involving exons 23-24.

 

Treatment and Management
The patient’s care has focused on symptom management and optimizing quality-of-life. He is followed by a complex care team and multiple subspecialists. He is currently hospitalized with acute respiratory distress syndrome requiring tracheostomy placement.

 

Outcome and Follow-Up
Future plans include obtaining a sample (blood or skin biopsy) for mRNA studies. DNAs from deceased siblings are unavailable for segregation analysis.

 

Discussion
Three other cases of VPS50-related neurodevelopmental disorder, aged 18 months to 2 years, have been reported (Schneeberger et al 2021 and Hecher et al 2024). All had severe intellectual disability, progressive microcephaly, seizures, abnormal brain imaging, visual impairment, abnormal tone, neonatal cholestasis, and failure to thrive. One case had sensorineural hearing loss. Our patient is the oldest reported and shares these key features, but is unique in his history of polymicrogyria and absence of seizure activity past infancy. The deceased sibling with ventriculomegaly and partial agenesis of the corpus callosum likely had VPS50-related disorder. The relevance of holoprosencephaly in the family history remains unclear. Prior research identified decreased VPS50, VPS52, and VPS53 protein levels in patient-derived fibroblasts, linking VPS50 variants to impaired synaptic vesicle acidification, neurotransmitter cycling, and CNS development, which could explain the spectrum of neurodevelopmental and systemic symptoms observed.

 

Conclusion
VPS50-related neurodevelopmental disorder is an ultra-rare, multisystemic syndrome that includes severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal cholestasis, and failure to thrive. This fourth reported case expands the known clinical spectrum, and further research is needed to elucidate the disorder’s full phenotypic range.