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Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair
  1. Jillian P Casey1,2,
  2. Michael Nobbs3,
  3. Paul McGettigan4,
  4. SallyAnn Lynch5,
  5. Sean Ennis2,5
  1. 1National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
  2. 2School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
  3. 3Bristol Genetics Laboratory, Southmead Hospital, Westbury-on-Trym, Bristol, UK
  4. 4Animal Genomics Laboratory, UCD School of Agriculture, Food Science and Veterinary Medicine, College of Life Sciences, University College Dublin, Belfield, Dublin, Ireland
  5. 5National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
  1. Correspondence to Dr Sean Ennis, School of Medicine and Medical Sciences, Health Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland; sean.ennis{at}


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.

Conclusion 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.

  • Failure to thrive
  • DNA repair defect
  • Irish Traveller
  • natural killer cell deficiency
  • familial glucocorticoid deficiency
  • MCM4

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  • Funding National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Health Research Board Ireland, Medical Research Charities Groups, Irish Research Council for Science, Engineering and Technology, Science Foundation Ireland. The NCRC (SAC/95/07) supported the consumable costs for SNP genotyping. The HRB (HRA_HSR/2010/3) supported the cost of targeted next-generation sequencing. JPC was supported by NCRC and HRB (MRCG/2011/17) to undertake this project. She performed some of this work while supported by an EMBARK postgraduate award from IRCSET. PM is supported by SFI (07/SRC/B1156).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by Our Lady's Children's Hospital Ethics Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.