title: Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.
abstract: Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.
authors.affiliation: Department of Medical Genetics, University of British Columbia, and Child and Family Research Institute, Vancouver, Canada; Division of Medical Genetics, Department of Biomedicine, University Hospital, Basel, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Filges
authors.forename: E
authors.initials: E
authors.lastname: Nosova
authors.forename: E
authors.initials: E
authors.lastname: Bruder
authors.forename: S
authors.initials: S
authors.lastname: Tercanli
authors.forename: K
authors.initials: K
authors.lastname: Townsend
authors.forename: W T
authors.initials: WT
authors.lastname: Gibson
authors.forename: B
authors.initials: B
authors.lastname: Röthlisberger
authors.forename: K
authors.initials: K
authors.lastname: Heinimann
authors.forename: J G
authors.initials: JG
authors.lastname: Hall
authors.forename: C Y
authors.initials: CY
authors.lastname: Gregory-Evans
authors.forename: W W
authors.initials: WW
authors.lastname: Wasserman
authors.forename: P
authors.initials: P
authors.lastname: Miny
authors.forename: J M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002925:Ciliary Motility Disorders / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics*; D010641:Phenotype
chemical_list: D015513:Oncogene Proteins; C502598:KIF14 protein, human; D016547:Kinesins
keywords: KIF14; autosomal recessive; ciliopathy; cytokinesis; exome sequencing; fetal; lethal; prenatal