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Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families
  1. Kim Hynes1,2,
  2. Patrick Tarpey3,
  3. Leanne M Dibbens1,4,
  4. Marta A Bayly1,
  5. Samuel F Berkovic5,
  6. Raffaella Smith3,
  7. Zahyia Al Raisi1,
  8. Samantha J Turner5,
  9. Natasha J Brown6,7,
  10. Tarishi D Desai5,
  11. Eric Haan1,4,
  12. Gillian Turner8,
  13. John Christodoulou9,
  14. Helen Leonard10,
  15. Deepak Gill11,
  16. Michael R Stratton3,
  17. Jozef Gecz1,2,4,
  18. Ingrid E Scheffer5,6
  1. 1SA Pathology at the Women's and Children's Hospital, North Adelaide, SA, Australia
  2. 2School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia
  3. 3Wellcome Trust Sanger Institute, Hinxton, UK
  4. 4School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
  5. 5Epilepsy Research Centre and Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
  6. 6Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
  7. 7Barwon Health, Geelong, Victoria, Australia
  8. 8GOLD Service, Hunter Genetics, Waratah, New South Wales 2298, Australia
  9. 9Western Sydney Genetics Program, The Children's Hospital at Westmead and Disciplines of Paediatrics and Child Health & Genetic Medicine, University of Sydney, Sydney, Australia
  10. 10Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia
  11. 11TY Nelson Department of Neurology, The Children's Hospital at Westmead, Westmead, New South Wales, Australia
  1. Correspondence to Professor Jozef Gecz, SA Pathology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia; jozef.gecz{at}


Background Epilepsy and mental retardation limited to females (EFMR) is an intriguing X-linked disorder affecting heterozygous females and sparing hemizygous males. Mutations in the protocadherin 19 (PCDH19) gene have been identified in seven unrelated families with EFMR.

Methods and results Here, we assessed the frequency of PCDH19 mutations in individuals with clinical features which overlap those of EFMR. We analysed 185 females from three cohorts: 42 with Rett syndrome who were negative for MECP2 and CDKL5 mutations, 57 with autism spectrum disorders, and 86 with epilepsy with or without intellectual disability. No mutations were identified in the Rett syndrome and autism spectrum disorders cohorts suggesting that despite sharing similar clinical characteristics with EFMR, PCDH19 mutations are not generally associated with these disorders. Among the 86 females with epilepsy (of whom 51 had seizure onset before 3 years), with or without intellectual disability, we identified two (2.3%) missense changes. One (c.1671C→G, p.N557K), reported previously without clinical data, was found in two affected sisters, the first EFMR family without a multigenerational family history of affected females. The second, reported here, is a novel de novo missense change identified in a sporadic female. The change, p.S276P, is predicted to result in functional disturbance of PCDH19 as it affects a highly conserved residue adjacent to the adhesion interface of EC3 of PCDH19.

Conclusions This de novo PCDH19 mutation in a sporadic female highlights that mutational analysis should be considered in isolated instances of girls with infantile onset seizures and developmental delay, in addition to those with the characteristic family history of EFMR.

  • EFMR
  • seizures
  • intellectual disability
  • PCDH19
  • genetics
  • epilepsy and seizures

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  • Funding Other Funders: Wellcome Trust; National Health and Medical Research Council of Australia.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Child Youth and Women's Health Service, Adelaide, Australia.

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

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