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Whole exome sequencing identified a de novo missense variant in PLEKHG1 (c.370A>G (p.Thr124Ala)) in a preterm infant presenting with periventricular leukomalacia (PVL), suggesting a novel genetic contributor to white matter injury (1 proband PMID:39202455). The patient was born prematurely following dichorionic gestation with cotwin demise and developed PVL, a key risk factor for cerebral palsy and intellectual disability. In silico algorithms uniformly classified the variant as pathogenic, and the affected residue resides within the pleckstrin homology domain critical for CDC42 activation. PLEKHG1 encodes a Rho guanine nucleotide exchange factor required for CDC42-mediated endothelial mechanotransduction; disruption of this pathway may impair vascular responses to mechanical stress, promoting periventricular white matter lesions. No additional affected relatives or unrelated cases have been reported to date, and functional validation beyond computational prediction is lacking.
Gene–Disease AssociationLimitedSingle de novo proband ([PMID:39202455]) with PVL and no replication Genetic EvidenceLimitedOne de novo missense variant c.370A>G (p.Thr124Ala) in one patient without additional cases Functional EvidenceLimitedNo empirical functional assays; only in silico pathogenicity predictions |