title: Recurrence risk of epilepsy and mental retardation in females due to parental mosaicism of PCDH19 mutations.
abstract: OBJECTIVE
  Two unrelated families were ascertained in which sisters had infantile onset of epilepsy and developmental delay. Mutations in the protocadherin 19 (PCDH19) gene cause epilepsy and mental retardation limited to females (EFMR). Despite both sister pairs having a PCDH19 mutation, neither parent in each family was a heterozygous carrier of the mutation. The possibility of parental mosaicism of PCDH19 mutations was investigated.
  
  
  METHODS
  Genomic DNA from peripheral blood was obtained and sequenced for PCDH19 mutations. Parentage was confirmed by markers.
  
  
  RESULTS
  Both sister pairs have a mutation in PCDH19. Sister pair 1 has a missense mutation, c.74T>C, L25P, while sequence analysis indicates both of their parents are negative for the mutation. Diagnostic restriction enzyme analysis detected low-level mosaicism of the mutation in their mother. Sister pair 2 are half-sisters who share a mother and each has the missense PCDH19 mutation c.1019 A>G, N340S. The sequence chromatograph of their mother shows reduced signal for the same mutation. These data indicate maternal somatic and gonadal mosaicism of the PCDH19 mutation in both sister pairs. Phenotyping is suggestive of, and PCDH19 mutation detection is diagnostic for, the disorder EFMR in the affected girls.
  
  
  CONCLUSIONS
  We show that gonadal mosaicism of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of EFMR. This should be considered when providing genetic counseling for couples who have one affected daughter as they may risk recurrence of affected daughters and having sons at risk of transmitting EFMR.
authors.affiliation: Epilepsy Research Program, SA Pathology at Women's and Children's Hospital, 72 King William Rd., North Adelaide, SA 5006, South Australia. leanne.dibbens@health.sa.gov.au
authors.forename: L M
authors.initials: LM
authors.lastname: Dibbens
authors.forename: R
authors.initials: R
authors.lastname: Kneen
authors.forename: M A
authors.initials: MA
authors.lastname: Bayly
authors.forename: S E
authors.initials: SE
authors.lastname: Heron
authors.forename: T
authors.initials: T
authors.lastname: Arsov
authors.forename: J A
authors.initials: JA
authors.lastname: Damiano
authors.forename: T
authors.initials: T
authors.lastname: Desai
authors.forename: J
authors.initials: J
authors.lastname: Gibbs
authors.forename: F
authors.initials: F
authors.lastname: McKenzie
authors.forename: J C
authors.initials: JC
authors.lastname: Mulley
authors.forename: A
authors.initials: A
authors.lastname: Ronan
authors.forename: I E
authors.initials: IE
authors.lastname: Scheffer
mesh_terms: D000293:Adolescent; D015820:Cadherins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005192:Family Health; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D008297:Male; D009030:Mosaicism; D010290:Parents; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000091363:Protocadherins; D012008:Recurrence; D055815:Young Adult
chemical_list: D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins