VAPB

Inheritance Pattern: AD

Disease ID:MONDO:0008453

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0012077

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0012077

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012077

Submitter: ClinGen

VAPB was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) 8 and Finkel-type spinal muscular atrophy (SMA) in 2004 (Nishimura et al., PMID: 15372378). ALS 8 is a phenotypic description of ALS caused by variants in the VAPB gene. It is characterised by a predominantly lower motor neuron presentation often accompanied by tremor. Finkel-type SMA is an adult onset, autosomal dominant form of SMA. ALS 8 and SMA occurs in families that share a common founder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability (there was high inter and intrafamilial variability). Therefore, the following disease entities have been lumped into one disease entity, ALS 8 (OMIM: 608627) and Finkel-type SMA (OMIM: 182980). 10 variants (missense and small deletion) that have been reported in 31 probands in 13 publications (PMIDs: 15372378, 16967488, 18322265, 20447143, 20577002, 26566915, 27978769, 29560381, 28993872, 20940299, 23446633, 22878164, 16729899) are included in this curation. Segregation analysis identified a candidate gene region on Chromosome 20 and all genes were sequenced in the candidate region in order to identity the P56S variant in VAPB, which is responsible for the majority of cases. The maximum score for genetic evidence (12 pts.) has been reached and the mechanism of pathogenicity appears to be gain of function. This gene-disease association is also supported by animal models, expression studies, and in vitro functional assays (PMIDs: 24271015, 26362257, 33972508, 18701194, 17804640, 17804640). There is a knock-in mouse model of VAPB P56S with motor defects detected by the rotarod and inverted grid tests, in addition to evidence of altered muscle cell phenotype and denervation. A fly model with a VAPB gene deletion rescued with P56S vap expression also found evidence of nerve conduction defects, reduced lifespan, and jumping and flight defects. A muscle biopsy of tissue from someone with ALS 8 showed impaired unfolded protein response and autophagy in cells cultured muscle cells. Expression studies show that VAPB is expressed abundantly in lower motor neurons and its expression is reduced in people with sporadic ALS. In summary, VAPB is definitively associated with autosomal dominant ALS and Finkel-type SMA. 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 ALS GCEP on December 14, 2021 (SOP Version 8).