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WDR4 causes an autosomal recessive form of Galloway-Mowat syndrome, marked by microcephaly, global developmental delay, intellectual disability, growth deficiency and proteinuria. In a single consanguineous Indian family, whole exome sequencing and homozygosity mapping identified a homozygous splice-site mutation c.454-2A>C in WDR4 that segregated with disease in three affected siblings (PMID:30079490) and two additional relatives (PMID:30079490).
WDR4 encodes a tRNA N7-methylguanosine methyltransferase subunit, and loss of function likely impairs tRNA modification in neurons and podocytes. Although enzyme dysfunction plausibly underlies both neurodevelopmental and glomerular defects, no direct functional assays in patient samples have been reported. Key take-home: identification of recessive WDR4 splice variants expands the molecular diagnosis of GAMOS and highlights tRNA methylation as a therapeutic target.
Gene–Disease AssociationLimitedSingle consanguineous family with three probands and two segregating relatives ([PMID:30079490]) Genetic EvidenceLimitedOne homozygous splice-site variant c.454-2A>C in three siblings segregating with disease ([PMID:30079490]) Functional EvidenceLimitedProposed tRNA methylation defect based on enzyme function, but no direct patient-derived functional studies |