Recessive Mutations in KIF12 Cause High Gamma‐Glutamyltransferase Cholestasis

Abstract

Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma‐glutamyltransferase (GGT) cholestasis. Here, we report whole‐exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 ( KIF12 ). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion : Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children.

Clinical exome sequencing reveals a novel pathogenic variant in KIF12 underlying cholestasis with highly variable phenotypes

“…Uptill now, four pathogenic variants (c.463C>T: p.(Arg155*), c.655C>T: p.(Arg219*), c.610G>A: p.(Val204Met), and c.482‐4_500del: p.?) have been reported in KIF12 in patients originating from Turkey, Afghanistan, Syria, Iraq and Saudi Arabia 2–4 . All the reported families have consanguinity and the identified variants were homozygous in patients.…”

“…Previously, none of the KIF12‐associated cases have shown nail clubbing 2–4 . Intra and inter‐familial variability in the phenotypes have been reported.…”

Exome Sequencing in Clinical Hepatology

“…Other independent studies have consistently reported WES diagnostic rates of 20% or higher . Furthermore, we and others have successfully combined WES with deep phenotyping (i.e., detailed characterization of each patient's phenotypic features) to identify the underlying genetic defects in infants and children with idiopathic liver diseases, including children with liver failure of indeterminate etiology . Astute clinical annotation (i.e., comprehensive phenotype description of the patient) is central to harnessing the maximal potential of genomic data .…”

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

“…In 2019, Unlusoy Aksu et al described three patients with PFIC features, high GGT and BAs, neonatal cholestasis and mutations in the KIF12 gene [ 97 ]. In the same year, Maddirevula et al reported four patients with a similar history of elevated GGT and neonatal cholestasis [ 17 ].…”