PT - JOURNAL ARTICLE AU - Hecher, Laura AU - Gorski-Alberts, Esther AU - Begemann, Matthias AU - Herwig, Johanna AU - Lausberg, Eva AU - Hillebrand, Georg AU - Volk, Alexander E AU - Kurth, Ingo AU - Kraft, Florian AU - Kutsche, Kerstin TI - Complex structural variation and nonsense variant <em>in trans</em> cause <em>VPS50</em>-related disorder AID - 10.1136/jmg-2024-109983 DP - 2024 Jun 14 TA - Journal of Medical Genetics PG - jmg-2024-109983 4099 - http://jmg.bmj.com/content/early/2024/06/18/jmg-2024-109983.short 4100 - http://jmg.bmj.com/content/early/2024/06/18/jmg-2024-109983.full AB - 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&gt;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.