Submission Details

The VPS13B gene has been associated with the Autosomal Recessive condition, Cohen Syndrome, using the ClinGen Clinical Validity Framework as of 08/02/2018. This association was made using case-level data only. More than 150 variants in this gene, mostly nonsense and frameshift, but also including large deletions and missense variants, have been reported in humans. Cohen syndrome is characterized chiefly by intellectual disability and developmental delay, typical facial gestalt, pigmentary retinopathy and intermittent neutropenia. It is over-represented in the Finnish population, likely due to a founder effect, with patients exhibiting a homogeneous phenotype. VPS13B was first associated with this disease in humans as early as 2003 (Kolehmainen et al., PMID: 12730828).

Summary of Case Level Data: 12 POINTS The association is seen in at least 10 probands in 6 publications (PMIDs: 12730828, 15173253, 26104215, 29149870, 19006247, 29758347). Variants in this gene segregated with disease in 41 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism for disease is homozygous loss of function, with the majority of variants observed being null variants (frameshift/nonsense) and predicted or shown to result in reduced mRNA product due to nonsense-mediated decay (PMID: 21865173).

Summary of Experimental Data: 0.5 POINTS The pathological mechanism of the disease is not clearly understood, and experimental evidence elucidating VPS13B protein function is still emerging. This gene is found to be expressed ubiquitously in most human tissues, but at higher levels in specific areas of the brain (PMID: 15173253). It is also shown that two alternatively spliced transcripts (using exon 28 and 28b) of the gene are expressed exclusively in the brain and retina, while only one (using exon 28b) is expressed ubiquitously (PMID: 19006247). Many alternatively spliced transcripts exist for VPS13B, but none of the variants reported in this gene are exclusive to specific transcripts.

The loss of VPS13B by siRNA silencing has been found to reduce neurite length, showing that loss of function variations in this gene result in functional alteration of the protein (PMID: 25492866). In addition, VPS13B is also shown to localize to the Golgi apparatus, interacting with Golgi-associated proteins, and be involved in Golgi assembly and glycosylation of other proteins (PMID: 21865173, 24334764). Although there is little experimental evidence supporting this gene-disease relationship at this time, the abundance of genetic evidence compels a definitive link between VPS13B and Cohen syndrome.

In summary, the VPS13B - Autosomal Recessive Cohen Syndrome gene-disease relationship is Definitive. 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 Autism and Intellectual Disability Expert Panel on 08/15/2018.

VPS13B was first reported in relation to autosomal recessive Cohen syndrome in 2003 (Kolehmainen et al., PMID: 12730828). More than 150 variants in VPS13B, mostly nonsense and frameshift, but also large deletions and missense variants, have been reported. Cohen syndrome is characterized by developmental delay, intellectual disability, typical facial gestalt, pigmentary retinopathy and intermittent neutropenia. It is over-represented in the Finnish population, likely due to a founder effect, with patients exhibiting a homogeneous phenotype.

Eight variants (frameshift, nonsense and missense) that have been reported in nine probands in six publications (PMIDs: 12730828, 15173253, 19006247, 26104215, 29149870, 29758347) are included in this curation. Variants in this gene segregated with disease in 41 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is biallelic loss of function, with the majority of variants observed being null variants (frameshift and nonsense) and predicted or shown to result in reduced mRNA product due to nonsense-mediated decay (PMID: 21865173).

Experimental evidence elucidating VPS13B protein function is still emerging. This gene-disease relationship is supported by studies showing that Vps13b knockdown in primary rat hippocampal neurons reduces neurite length (PMID: 25492866). VPS13B localizes to the Golgi apparatus, where it interacts with Golgi-associated proteins and is involved in Golgi assembly and glycosylation of other proteins (PMID: 24334764).

In summary, there is definitive evidence supporting the relationship between VPS13B and autosomal recessive Cohen syndrome. 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 Intellectual Disability and Autism Gene Curation Expert Panel on August 15, 2018 (SOP Version 6).