{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:22:08Z","timestamp":1791339728182,"version":"4.3.1"},"reference-count":17,"publisher":"BMJ","issue":"9","funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KU 1240\/17-1"],"award-info":[{"award-number":["KU 1240\/17-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,6,1]]},"published-print":{"date-parts":[[2024,9]]},"abstract":"<jats:p>Homozygous <jats:italic>VPS50<\/jats:italic> variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. <jats:italic>VPS50<\/jats:italic> 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 <jats:italic>VPS50<\/jats:italic> variants. She carried a paternally inherited heterozygous nonsense c.13A&gt;T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3\u2009Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428\u2009kb deletion at the telomeric inversion breakpoint encompasses the entire <jats:italic>VPS50<\/jats:italic> gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both <jats:italic>VPS50<\/jats:italic> 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 <jats:italic>VPS50<\/jats:italic> pathogenic variants. The <jats:italic>VPS50<\/jats:italic>-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.<\/jats:p>","DOI":"10.1136\/jmg-2024-109983","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T13:20:20Z","timestamp":1718371220000},"page":"833-838","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Complex structural variation and nonsense variant <i>in trans<\/i> cause <i>VPS50<\/i>-related disorder"],"prefix":"10.1136","volume":"61","author":[{"given":"Laura","family":"Hecher","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Gorski-Alberts","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Kinder- und Jugendmedizin, Neonatologie und P\u00e4diatrische Intensivmedizin, Klinikum Itzehoe, Itzehoe, Schleswig-Holstein, 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