Complex structural variation and nonsense variant in trans cause VPS50-related disorder

Journal of Medical Genetics, vol. 61, pp. 833–838

Abstract

Homozygous VPS50 variants have been previously 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 complex. 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 characterised a structural variant 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 a 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. 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.

Authors 10

1. Laura Hecher

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2. Esther Gorski-Alberts

   Klinikum Itzehoe

   Affiliation as printed

   Klinik für Kinder- und Jugendmedizin, Neonatologie und Pädiatrische Intensivmedizin, Klinikum Itzehoe, Itzehoe, Schleswig-Holstein, Germany

3. Matthias Begemann Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

4. J. Herwig

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

5. Eva Lausberg Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

6. Georg Hillebrand

   Klinikum Itzehoe

   Affiliation as printed

   Klinik für Kinder- und Jugendmedizin, Neonatologie und Pädiatrische Intensivmedizin, Klinikum Itzehoe, Itzehoe, Schleswig-Holstein, Germany

7. Alexander Erich Volk

   University Medical Center Hamburg-Eppendorf

   Affiliation as printed

   Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

8. Ingo Kurth Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

9. Florian Kraft Aachen Institute for Human Genetics and Genomic Medicine Medical Faculty

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany

10. Kerstin Kutsche corresponding

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    University Medical Center Hamburg-Eppendorf, Institute of Human Genetics, Hamburg, Germany