Submission Details

VPS11 was first reported in relation to autosomal recessive hypomyelinating leukodystrophy 12 (HLD12) in 2015 (OMIM: 608549, PMID: 26307567) and later in association with autosomal recessive dystonia 32 in 2021 (OMIM: 619637. PMID: 33452836). VPS11 encodes class C core vacuole/endosome tethering (CORVET) and homotypic fusion and protein sorting (HOPS) protein complexes involved in membrane trafficking and autophagy (PMID:31015428). HLD12 is clinically characterized by global developmental delay, microcephaly, hypotonia, intellectual disability, cerebral visual impairment, hearing loss, seizures, and dystonia (PMID: 27120463). Neuroimaging shows hypomyelination, diminished corpus callosum, and cerebellar atrophy (PMID: 33452836, 33452836). Two distinct missense variants have been reported in individuals affected with HLD12, and functional studies of both variants showed loss-of-function. A single case has been reported of adult-onset neurodegenerative disorder characterized by dystonia, dysphagia, and anarthria. Neuroimaging displayed mild brain atrophy with basal ganglia involvement and symmetrical bipallidal hypointensity. Functional studies of the homozygous variant in this individual showed loss-of-function (PMID: 33452836). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance. Further, we found that the phenotypes likely represent a clinical spectrum. Therefore, the HLD12 and DYT32 disease entities have been lumped into one disease entity, VPS11 Related Neurologic Disorder. Three unique variants have been reported in the homozygous state in 9 probands across 4 publications and are included in this curation (PMIDs: 27120463, 33452836, 26307567, 27473128). Of note, one variant (c.2536T>G (p.Cys846Gly)) was observed in seven probands of Ashkenazi Jewish descent and is likely a founder variant in this population. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by a naturally-occurring mammalian animal model (dog) as well as a vertebrate model (zebrafish). Similar to humans, the dog model presents with ataxia and neuroaxonal dystrophy and is predicted to affect autophagy (PMID: 29945969). The zebrafish model closes capitulates human disease, demonstrating hypomyelination, visual, and sensorimotor abnormalities (PMID:35241734) In summary, there is definitive evidence supporting the relationship between VPS11 and the disease entity now known as VPS11-related neurological disorder (MONDO:0100617). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy GCEP on the meeting date March 5, 2025 (SOP Version 11).