Submission Details

The MET gene, which encodes a receptor tyrosine kinase, has been reported in the literature in association with papillary renal cell carcinoma, deafness, and neurodevelopmental disorders (autism spectrum disorder [ASD] and developmental disorders). The relationships between MET and both papillary renal cell carcinoma and nonsyndromic genetic deafness have previously been evaluated by other ClinGen gene curation expert panels; please see those curation summaries for further information. This curation is focused on the relationship between MET and complex neurodevelopmental disorder. The available genetic evidence for MET in the context of neurodevelopmental disorders can be divided into two categories: association studies of common genetic variants and large cohort studies of rare variants. Between 2006 and 2010, several studies suggested that common noncoding variants in MET were associated with autism susceptibility (PMIDs: 17053076, 19002214, 19681062, 20615438). However, these association studies were all extremely underpowered and their findings were not validated in a very large GWAS study in ASD (PMID: 30804558). Four rare de novo missense variants in the MET gene have also been observed in individuals with ASD or developmental disorders (PMIDs: 25533962, 29346770, 28714951). Three of these variants have been observed in multiple individuals in gnomAD v2.1.1. and were therefore not scored. The other missense variant was not present in gnomAD, but in the absence of functional evidence of pathogenicity was also not scored. A fifth case involved a boy with autism, severe language delay, and learning disabilities and an intragenic deletion including exons 12-15 of the MET gene (PMID: 24909855). The proband had two siblings with learning disabilities, language and social impairment, but only one carried the deletion. Further, while this variant was not inherited from the proband’s mother, the father was unavailable for testing or clinical evaluation. Because of this, we opted not to score this variant. The experimental evidence for MET includes expression studies and mouse models, which evaluated different brain subregions, synaptic transmission and behavioral alterations (PMIDs: 7651534, 26523156, 20853516, 21509596, 21490227, 25471559, 26290232). The Met full knockout is lethal (PMID: 7651534), hence, the available mouse models were conditional knockouts for different brain cell types (PMID: 29188052). Met mutant mice showed abnormal dendritic spine morphology (PMIDs: 20853516, 21509596) and hypoactivity across several behavioral tasks (PMID: 26523156). However, sociability and social novelty preference were intact in the mutant animals and there was no evidence for increased anxiety or repetitive behaviors (PMID: 26523156). In the absence of human genetic evidence, this experimental evidence was not scored. Overall, there is currently no convincing evidence to support a relationship between MET and complex neurodevelopmental disorder, so this gene-disease relationship is disputed. The ClinGen Intellectual Disability and Autism Gene Curation Expert Panel approved this classification on 01/19/2021 (SOP Version 8).