title: Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies.
abstract: We studied two brothers who presented in the newborn period with cardiac, renal, and hepatic anomalies that were initially suggestive of ALGS, although no mutations in JAG1 or NOTCH2 were identified. Exome sequencing demonstrated compound heterozygous mutations in the NEK8 gene (Never in mitosis A-related Kinase 8), a ciliary kinase indispensable for cardiac and renal development based on murine studies. The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain. The RCC1 domain is crucial for localization of the NEK8 protein to the centrosomes and cilia. Mutations in NEK8 have been previously reported in three fetuses (from a single family) with renal-hepatic-pancreatic dysplasia 2 (RHPD2), similar to Ivemark syndrome, and in three individuals with nephronophthisis (NPHP9). This is the third report of disease-causing mutations in the NEK8 gene in humans and only the second describing multi-organ involvement. The clinical features we describe differ from those in the previously published report in that (1) a pancreatic phenotype was not observed in the individuals reported here, (2) there were more prominent cardiac findings, (consistent with observations in murine models), and (3) we observed bile duct hypoplasia rather than ductal plate malformation. The patients reported here expand our understanding of the NEK8-associated phenotype. Our findings highlight the variable phenotypic expressivity and the spectrum of clinical manifestations due to mutations in the NEK8 gene.
authors.affiliation: Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Rajagopalan
authors.affiliation: Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Grochowski
authors.affiliation: Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Gilbert
authors.affiliation: Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Falsey
authors.affiliation: Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Karlene
authors.initials: K
authors.lastname: Coleman
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Rene
authors.initials: R
authors.lastname: Romero
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Loomes
authors.affiliation: Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David A
authors.initials: DA
authors.lastname: Piccoli
authors.affiliation: Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Devoto
authors.affiliation: Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
mesh_terms: D000015:Abnormalities, Multiple; D059472:Exome; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney / Q000002:abnormalities; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000235:genetics*; D008099:Liver / Q000002:abnormalities; D008107:Liver Diseases / Q000151:congenital* / Q000175:diagnosis; D008297:Male; D009154:Mutation; D000072379:NIMA-Related Kinases; D010179:Pancreas / Q000002:abnormalities; D011494:Protein Kinases / Q000235:genetics*; D035781:Siblings
chemical_list: D011494:Protein Kinases; C458529:NEK8 protein, human; D000072379:NIMA-Related Kinases
keywords: NEK8; exome sequencing; nephronopthisis; renal-pancreatic-hepatic dysplasia