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KIF12 encodes a microtubule-dependent kinesin motor protein critical for intracellular cargo transport in hepatocytes. Biallelic loss-of-function variants in KIF12 have been linked to an autosomal recessive form of neonatal cholestasis characterized by markedly elevated gamma-glutamyltransferase (GGT) levels.
In a 2019 study, two unrelated pediatric patients from consanguineous families presented with severe cholestasis and high GGT; both harbored rare homozygous KIF12 variants: a truncating c.1069C>T (p.Arg357Ter) and a missense c.1024G>A (p.Val342Met) ([PMID:30976738]). An older sibling homozygous for c.1024G>A (p.Val342Met) also exhibited cholestasis, confirming segregation in a multiplex family ([PMID:30976738]).
In a subsequent series of six affected children from four additional unrelated families, homozygous truncating KIF12 variants were identified, notably c.1069C>T (p.Arg357Ter), further establishing the genetic basis of this phenotype ([PMID:34555379]).
Overall, nine probands across six unrelated families have been described, with segregation evidence in one additional affected relative. The variant spectrum includes at least one recurrent nonsense allele and one missense allele, all in the homozygous state in affected individuals.
Functional assessment of liver tissue from affected children demonstrated disrupted hepatocyte polarity by immunofluorescence, consistent with impaired canalicular architecture and cholestasis ([PMID:34555379]). KIF12 deficiency likely leads to cholestasis via loss-of-function, disrupting microtubule-dependent motor activity essential for bile canaliculi formation.
Together, the genetic and experimental data support a strong autosomal recessive gene–disease relationship between KIF12 and high GGT cholestasis. Identification of biallelic KIF12 variants should inform diagnostic evaluation and guide family counseling.
Key Take-home: Biallelic KIF12 loss-of-function variants cause high GGT cholestasis via impaired hepatocyte polarity, warranting their inclusion in pediatric cholestasis gene panels.
Gene–Disease AssociationStrong9 probands across 6 unrelated families; segregation in 1 affected relative; concordant functional data Genetic EvidenceStrongAutosomal recessive inheritance with 9 homozygous probands in 6 families; segregation in 1 additional relative; variant spectrum includes one recurrent truncating and one missense allele Functional EvidenceModerateImmunofluorescence studies in patient liver demonstrate disrupted hepatocyte polarity consistent with bile canalicular defects |