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Complex structural variation and nonsense variant in trans cause VPS50-related disorder
  1. Laura Hecher1,
  2. Esther Gorski-Alberts2,
  3. Matthias Begemann3,
  4. Johanna Herwig1,
  5. Eva Lausberg3,
  6. Georg Hillebrand2,
  7. Alexander E Volk1,
  8. Ingo Kurth3,
  9. Florian Kraft3,
  10. Kerstin Kutsche1
  1. 1Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  2. 2Klinik für Kinder- und Jugendmedizin, Neonatologie und Pädiatrische Intensivmedizin, Klinikum Itzehoe, Itzehoe, Schleswig-Holstein, Germany
  3. 3Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH Aachen University Hospital, Aachen, Germany
  1. Correspondence to Professor Kerstin Kutsche, University Medical Center Hamburg-Eppendorf, Institute of Human Genetics, Hamburg, Germany; kkutsche{at}


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.

  • Exome Sequencing
  • Gene Rearrangement
  • Human Genetics
  • Nervous System Diseases

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  • X @contender403, @flokraft_

  • FK and KK contributed equally.

  • Correction notice The article has been corrected since it was published online. The equal contributorship statement has been added.

  • Contributors Patient recruitment: EG-A and GH. Clinical evaluation: LH, EG-A, GH, JH and AEV. Data analysis and interpretation: LH, MB, EL, IK, FK and KK. Writing: LH, E-GA, GH, MB, EL, JH, AEV, IK, FK and KK. Supervision: KK.

  • Funding This work was supported by the Deutsche Forschungsgemeinschaft (KU 1240/17-1 to Kerstin Kutsche).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.