title: Mutations in WDR19 encoding the intraflagellar transport component IFT144 cause a broad spectrum of ciliopathies.
abstract: BACKGROUND
  An emerging number of clinically and genetically heterogeneous diseases now collectively termed ciliopathies have been connected to the dysfunction of primary cilia. We describe an 8-year-old girl with a complex phenotype that did not clearly match any familiar syndrome.
  
  
  METHODS
  Hypotonia, facial dysmorphism and retardation were noted shortly after birth. Other features included short stature, mild skeletal anomalies, strabism, deafness, subdural hygroma, hepatosplenomegaly and end-stage renal failure. Renal biopsy revealed tubular atrophy, interstitial fibrosis and segmental glomerulosclerosis. After exclusion of a chromosomal abnormality by array-comparative genomic hybridization (CGH), we performed next-generation sequencing (NGS) using a customized panel that targeted 131 genes known or hypothesized to cause ciliopathies. We identified the novel homozygous WDR19 mutation c.1483G > C (p.Gly495Arg) that affects an evolutionarily highly conserved residue in the intraflagellar transport protein IFT144, is absent from databases and is predicted to be pathogenic by all bioinformatic sources used.
  
  
  CONCLUSIONS
  Mutations in WDR19 encoding the intraflagellar transport component IFT144 have recently been described in single families with the clinically overlapping skeletal ciliopathies Jeune and Sensenbrenner syndromes, combined or isolated nephronophthisis (NPHP) and retinitis pigmentosa (RP) (Senior-Loken syndrome). Our patient emphasizes the usefulness and efficiency of a comprehensive NGS panel approach in patients with unclassified ciliopathies. It further suggests that WDR19 mutations can cause a broad spectrum of ciliopathies that extends to Jeune and Sensenbrenner syndromes, RP and renal NPHP-like phenotypes.
authors: Department of Pediatrics, Children's Hospital Memmingen, Memmingen, Germany.
authors: Henry
authors: H
authors: Fehrenbach
authors: Christian
authors: C
authors: Decker
authors: Tobias
authors: T
authors: Eisenberger
authors: Valeska
authors: V
authors: Frank
authors: Tobias
authors: T
authors: Hampel
authors: Ulrike
authors: U
authors: Walden
authors: Kerstin U
authors: KU
authors: Amann
authors: Ingrid
authors: I
authors: Krüger-Stollfuß
authors: Hanno J
authors: HJ
authors: Bolz
authors: Karsten
authors: K
authors: Häffner
authors: Martin
authors: M
authors: Pohl
authors: Carsten
authors: C
authors: Bergmann
mesh_terms: D002648:Child; D002923:Cilia / Q000473:pathology*; D003598:Cytoskeletal Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D006128:Growth / Q000502:physiology; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C486869:WDR19 protein, human