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Warburg Micro syndrome is an autosomal recessive multisystem developmental disorder marked by postnatal microcephaly, severe visual impairment, congenital cataracts, and spastic tetra- or paraplegia. Genetic etiologies include biallelic loss-of-function variants in RAB3GAP1, RAB3GAP2, TBC1D20, and RAB18, which encode regulators of membrane trafficking in neuronal and ocular tissues. Clinical phenotypes overlap indistinguishably across these genes, implicating a shared pathway for neurodevelopment and eye formation ([PMID:21473985]).
Autosomal recessive RAB18 mutations were first identified by autozygosity mapping in five consanguineous families lacking RAB3GAP1/2 variants and one compound heterozygous family, totaling six unrelated probands with Warburg Micro syndrome ([PMID:21473985]). A subsequent survey of 153 Warburg Micro and Martsolf families detected RAB18 variants in approximately 5% of cases, adding an estimated eight additional probands with confirmed pathogenic alleles ([PMID:23420520]). This yields at least 14 probands with biallelic RAB18 variants supporting a recessive inheritance model.
The variant spectrum in RAB18 comprises missense, in-frame deletion, anti-termination, and predicted frameshift alleles. Key examples include the recurrent founder missense c.71T>A (p.Leu24Gln), an in-frame deletion c.277_279del (p.Arg93del), and the stop-codon extension c.619T>C (p.Leu206_Ter207insGlnThrLeuGlyAsnSerIleSerCysIlePheAspGlnIleValThrSerPheCysIle) ([PMID:21473985]).
Segregation analysis demonstrated complete cosegregation of RAB18 variants with disease in multiple affected sibships, notably four Pakistani families sharing the c.71T>A (p.Leu24Gln) founder allele. Affected_relatives: 4.
Functional assays established RAB18 mutants as null alleles: both Leu24Gln and Arg93del proteins failed to bind guanine nucleotides, and zebrafish rab18 knockdown recapitulated ocular and brain anomalies seen in patients ([PMID:21473985]). Additional biochemical studies revealed that loss of RAB3GAP or TBC1D20 dysregulates RAB18 localization, suggesting a model in which these GAP/GEF regulators are essential for RAB18 function and microsomal trafficking ([PMID:26063829]).
Multiple mouse models further corroborate the pathogenic mechanism. Rab18-/- mice exhibit congenital nuclear cataracts, atonic pupils, hind limb weakness, and progressive neurodegeneration. Cellular analyses show lipid droplet accumulation, altered hepatic TC and TG levels, impaired fatty acid release, and disrupted autophagy signaling in liver and neuronal tissues ([PMID:24764192]; [PMID:40157288]). Complementary studies reveal that Rab18 associates with lysosomes and modulates autophagic flux in neurons, with Rab7 upregulation as a compensatory response, linking lysosomal and autophagy defects to the Warburg Micro phenotype ([PMID:30721447]).
Together, robust autosomal recessive segregation, a diverse pathogenic variant spectrum, and concordant in vivo and in vitro functional evidence establish a Strong gene–disease relationship between RAB18 and Warburg Micro syndrome. Genetic evidence is rated Moderate based on 14 probands with biallelic variants, and functional evidence is rated Moderate with multiple animal and cellular models validating the loss-of-function mechanism.
Key Take-home: Sequencing of RAB18 should be included in diagnostic panels for patients presenting with congenital cataracts, severe visual impairment, microcephaly, and spasticity, as biallelic loss-of-function variants cause Warburg Micro syndrome.
Gene–Disease AssociationStrong14 probands, multi-family segregation, concordant functional data Genetic EvidenceModerate6 families in initial mapping and ~8 additional families with confirmed biallelic variants Functional EvidenceModerateBiochemical null assays, zebrafish and multiple mouse models recapitulate key phenotypes |