Neuropediatrics 2024; 55(S 01): S1-S25
DOI: 10.1055/s-0044-1791910
Neurometabolische und Neurogenetische Erkrankungen

A Complex Structural Variation and a Nonsense Variant in trans Cause the VPS50-Related Disorder

Authors

  • L. Hecher

    1   Institut für Humangenetik - Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

  • E. Gorski-Alberts

    3   Klinik für Kinder- und Jugendmedizin - Klinikum Itzehoe, Itzehoe, Germany

  • M. Begemann

    4   Institut für Humangenetik - Uniklinik RWTH Aachen, Aachen, Germany

  • J. Herwig

    1   Institut für Humangenetik - Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

  • E. Lausberg

    4   Institut für Humangenetik - Uniklinik RWTH Aachen, Aachen, Germany

  • G. Hillebrand

    3   Klinik für Kinder- und Jugendmedizin - Klinikum Itzehoe, Itzehoe, Germany

  • A. Volk

    1   Institut für Humangenetik - Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

  • I. Kurth

    4   Institut für Humangenetik - Uniklinik RWTH Aachen, Aachen, Germany

  • F. Kraft

    4   Institut für Humangenetik - Uniklinik RWTH Aachen, Aachen, Germany

  • K. Kutsche

    1   Institut für Humangenetik - Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
Further Information
Also available at
 

Background/Purpose: Homozygous VPS50 variants have been described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis. VPS50 encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52, and VPS53, are also shared by the Golgi-associated retrograde protein (GARP) complex. We report on the third patient with biallelic VPS50 variants.

Methods: Clinical data were collected and evaluated. Exome sequencing, long-read genome sequencing, and variant validation were performed. RNA isolation, cDNA synthesis, and qualitative and quantitative transcript analysis were performed. To analyze the protein level of VPS50, VPS52, and VPS53 in fibroblasts of the patient and two controls, we performed immunoblot analysis.

Results: We report on an 18-month-old female patient with biallelic VPS50 variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterized a complex rearrangement with a 4.3-Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428-kb deletion at the telomeric inversion breakpoint encompasses the entire VPS50 gene. We demonstrated deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both VPS50 variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient.

Conclusion: These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with VPS50 pathogenic variants. The VPS50-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis, and failure to thrive. The disease is potentially fatal in early childhood.



Publication History

Article published online:
08 October 2024

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany