Monogenic short stature

Gene: VPS50

Red List (low evidence)

Comment on list classification: As per current Test Directory criteria for this panel, presence of microcephaly in an individual excludes R453 Monogenic short stature testing. While there are 3 individuals reported with short stature and biallelic VPS50 variants, including two individuals with more than -2 Z, all 3 had microcephaly as well. Hence, this gene should be Grey and tagged curated_removed on this panel.

Created: 22 Apr 2026, 5:03 p.m. | Last Modified: 22 Apr 2026, 5:03 p.m.

Panel Version: 1.35

3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Her height was 77cm at 18 months (-1.69 Z). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).

Created: 22 Apr 2026, 4:54 p.m. | Last Modified: 22 Apr 2026, 4:59 p.m.

Panel Version: 1.34

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216

Publications

• 38876772

Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.

Created: 1 Oct 2021, 2:26 p.m. | Last Modified: 1 Oct 2021, 2:37 p.m.

Panel Version: 1.82

I don't know

Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature

Created: 13 Aug 2021, 1:35 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum

Publications

• 34037727