PLEKHG5 was first reported in relation to autosomal recessive distal spinal muscular atrophy 4 in 2007 (Maystadt et al., PMID:17564964). Spinal muscular atrophy, distal, autosomal recessive, 4 (OMIM:611067) and Charcot-Marie-Tooth disease, recessive intermediate C (OMIM:615376) have been lumped into one disease entity, neuromuscular disease (MONDO:0019056), for this curation. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, no difference in inheritance pattern, and overlapping phenotypes.
Five variants (missense, frameshift, and nonsense) that have been reported in four probands in three publications (PMIDs:17564964, 23777631, 23844677) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was nearly reached. Mutations cluster in the Pleckstrin-Homology Domain and Rho-Guanine Exchange Factor Domain. The mechanism of pathogenicity is reported to be loss of function and involves aggregate formation. Case-level functional data supporting pathogenicity include luciferase reporter assays showing significant reduction of nuclear factor-κB (NFkB) signaling activation and immunofluorescence assays displaying formation of aggregates in cells expressing mutant PLEKHG5 (PMIDs:17564964, 23844677). This gene-disease relationship is also supported by a PLEKHG5 knockout mouse models (PMID:29084947). PLEKHG5 gene inactivation in mice resulted in a late-onset motoneuron disease, characterized by degeneration of axon terminals. An experiment treating PLEKHG5 deficient murine motoneurons with constitutively activated Rab26 rescued NFkB activation levels, but was not included in the score of this curation (PMID:29084947). Rab26 is not a direct gene product of PLEKHG5 and therefore not congruent with ClinGen scoring guidelines for rescue models.
In summary, there is definitive evidence supporting the relationship between PLEKHG5 and autosomal recessive neuromuscular disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over. This classification was approved by the ClinGen Charcot-Marie-Tooth Disease GCEP on April 25, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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