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The gene PLEKHG3 (HGNC:20364) has been implicated in autism (MONDO_0005260) based on cytogenetic evidence from a de novo 1.5 Mb microdeletion at chromosome 14q23.2-23.3 (PMID:21360829). This microdeletion, identified in a 14‑year‑old proband, spans 15 genes including PLEKHG3, MTHFD1, CHURC1, and SPTB, and is associated with neurodevelopmental deficits consistent with autism as well as spherocytosis (HP:0004444). Despite the de novo occurrence, there are no additional extended segregation data or independent replication events available, limiting the strength of the association to a single reported case (PMID:21360829). The genetic evidence is further constrained by the lack of isolated, gene‑specific mutations for PLEKHG3; rather, its implication emerges solely from its inclusion within a larger deletion that encompasses multiple candidate genes. This limitation complicates the precise attribution of the autism phenotype to PLEKHG3 alone, as the contribution from other deleted genes cannot be excluded. Overall, while the de novo deletion provides an initial clue to a potential pathogenic role, the evidence remains preliminary.
In terms of experimental evidence, no specific functional assays have been conducted to evaluate the pathogenicity of PLEKHG3 in autism. Functional studies available in the literature, such as those exploring fusion transcripts in other gene contexts, do not directly assess PLEKHG3 and thus offer little clarity on its molecular mechanism. The absence of a defined variant spectrum for PLEKHG3—in contrast to isolated coding changes like missense or loss‐of‑function mutations—further reduces the weight of the available genetic evidence. As such, functional corroboration through animal models, in vitro assays, or expression analyses is currently lacking. Integration of the genetic and limited experimental data suggests a constrained confidence level regarding the gene‑disease relationship. Key take‑home sentence: Although a de novo microdeletion implicates PLEKHG3 in autism, additional focused studies are required to firmly establish its clinical utility in diagnosis and risk assessment.
Gene–Disease AssociationLimitedBased on a single de novo microdeletion case (1 proband [PMID:21360829]) encompassing 15 genes, with no independent segregation or isolated gene-specific variant data. Genetic EvidenceLimitedThe microdeletion including PLEKHG3 lacks isolated coding variants or a recurrent variant spectrum, restricting attribution of autism risk solely to this gene (PMID:21360829). Functional EvidenceLimitedNo direct functional studies for PLEKHG3 in autism have been reported, and experimental data are largely derived from assessments of adjacent or fusion transcripts with other genes. |