Complex structural variation and nonsense variant in trans cause VPS50-related disorder
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Complex structural variation and nonsense variant in trans cause VPS50-related disorder. / Hecher, Laura; Gorski-Alberts, Esther; Begemann, Matthias; Herwig, Johanna; Lausberg, Eva; Hillebrand, Georg; Volk, Alexander E; Kurth, Ingo; Kraft, Florian; Kutsche, Kerstin.
In: J MED GENET, Vol. 61, No. 9, 29.08.2024, p. 833-838.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Complex structural variation and nonsense variant in trans cause VPS50-related disorder
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
N1 - © Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2024/8/29
Y1 - 2024/8/29
N2 - 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.
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>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.
U2 - 10.1136/jmg-2024-109983
DO - 10.1136/jmg-2024-109983
M3 - SCORING: Journal article
C2 - 38876772
VL - 61
SP - 833
EP - 838
JO - J MED GENET
JF - J MED GENET
SN - 0022-2593
IS - 9
ER -