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Critical consequences of finding three pathogenic mutations in an individual with recessive disease
  1. Sally Halsall1,
  2. Adeline K Nicholas2,
  3. Gemma Thornton2,
  4. Howard Martin1,
  5. C Geoffrey Woods2
  1. 1Genetics laboratories, East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  2. 2Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, UK
  1. Correspondence to Dr C Geoffrey Woods, Level 4, CIMR, Addenbrookes Hospital, Hills Road, Cambridge CB2 0XY, UK; cw347{at}


The authors report the unexpected finding of three different nonsense mutations in two unrelated individuals with a diagnosis of autosomal recessive primary microcephaly. In each case one phenotypically normal parent was found to carry two of the nonsense mutations, presumably in cis. This finding of ‘triple pathogenic mutations’ is of unknown incidence but has significant implication for genetic counselling. A failure to detect all three mutations could result in both false positive and false negative diagnoses in other family members. Both of these potential problems can be avoided by always genotyping the parents.

  • Clinical genetics
  • molecular genetics

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  • Funding Wellcome Trust.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Cambridge East Research Ethics Committee.

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