title: Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair.
abstract: BACKGROUND
  A study is presented of 10 children with a novel syndrome born to consanguineous parents from the Irish Traveller population. The syndrome is characterised by a natural killer (NK) cell deficiency, evidence of an atypical Fanconi's type DNA breakage disorder, and features of familial glucocorticoid deficiency (FGD). The NK cell deficiency probably accounts for the patients' recurrent viral illnesses. Molecular tests support a diagnosis of mosaic Fanconi's anaemia, but the patients do not present with any of the expected clinical features of the disorder. The symptomatic presentation of FGD was delayed in onset and may be a secondary phenotype. As all three phenotypes segregate together, the authors postulated that the NK cell deficiency, DNA repair disorder and FGD were caused by a single recessive genetic event.
  
  
  METHODS
  Single-nucleotide polymorphism homozygosity mapping and targeted next-generation sequencing of 10 patients and 16 unaffected relatives.
  
  
  RESULTS
  A locus for the syndrome was identified at 8p11.21-q11.22. Targeted resequencing of the candidate region revealed a homozygous mutation in MCM4/PRKDC in all 10 affected individuals. Consistent with the observed DNA breakage disorder, MCM4 and PRKDC are both involved in the ATM/ATR (ataxia-telangiectasia-mutated/ATM-Rad 3-related) DNA repair pathway, which is defective in patients with Fanconi's anaemia. Deficiency of PRKDC in mice has been shown to result in an abnormal NK cell physiology similar to that observed in these patients.
  
  
  CONCLUSIONS
  Mutations in MCM4/PRKDC represent a novel cause of DNA breakage and NK cell deficiency. These findings suggest that clinicians should consider this disorder in patients with failure to thrive who develop pigmentation or who have recurrent infections.
authors.affiliation: National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Casey
authors.forename: Michael
authors.initials: M
authors.lastname: Nobbs
authors.forename: Paul
authors.initials: P
authors.lastname: McGettigan
authors.forename: Sallyann
authors.initials: S
authors.lastname: Lynch
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D003241:Consanguinity; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007494:Ireland; D008297:Male; D064148:Minichromosome Maintenance Complex Component 4; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D022821:RNA Splice Sites; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C099243:MCM4 protein, human; D064148:Minichromosome Maintenance Complex Component 4