Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families.
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.


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.
Hynes
Kim
K
SA Pathology, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia.
Tarpey
Patrick
P
Dibbens
Leanne M
LM
Bayly
Marta A
MA
Berkovic
Samuel F
SF
Smith
Raffaella
R
Raisi
Zahyia Al
ZA
Turner
Samantha J
SJ
Brown
Natasha J
NJ
Desai
Tarishi D
TD
Haan
Eric
E
Turner
Gillian
G
Christodoulou
John
J
Leonard
Helen
H
Gill
Deepak
D
Stratton
Michael R
MR
Gecz
Jozef
J
Scheffer
Ingrid E
IE
D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics; D004827:Epilepsy / Q000150:complications / Q000235:genetics*; D005190:Family; D005191:Family Characteristics; D005260:Female; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000150:complications / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D000091363:Protocadherins; D017386:Sequence Homology, Amino Acid
D015820:Cadherins; C438605:PCDH19 protein, human; D000091363:Protocadherins