Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy.
OBJECTIVE
Mutations of the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause an X-linked encephalopathy with early onset intractable epilepsy, including infantile spasms and other seizure types, and a Rett syndrome (RTT)-like phenotype. Very limited information is available on the frequency and phenotypic spectrum associated with CDKL5 deletions/duplications. We investigated the role of CDKL5 deletions/duplications in causing early onset intractable epilepsy of unknown etiology in girls.


METHODS
We studied 49 girls with early onset intractable epilepsy, with or without infantile spasms, and developmental impairment, for whom no etiologic factors were obvious after clinical examination, brain magnetic resonance imaging (MRI) and expanded screening for inborn errors of metabolism. We performed CDKL5 gene mutation analysis in all and multiplex ligation dependent probe amplification assay (MLPA) in those who were mutation negative. Custom Array-comparative genomic hybridization (CGH), breakpoint polymerase chain reaction (PCR) analysis, and X-inactivation studies were performed in patients in whom MLPA uncovered a genomic alteration.


RESULTS
We found CDKL5 mutations in 8.2% (4 of 49) of patients and genomic deletions in 8.2% (4 of 49). Overall, abnormalities of the CDKL5 gene accounted for 16.3% (8 of 49) of patients.


CONCLUSIONS
CDKL5 gene deletions are an under-ascertained cause of early onset intractable epilepsy in girls. Genetic testing of CDKL5, including both mutation and deletion/duplication analysis, should be considered in this clinical subgroup.
Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer - University of Florence, Viale Pieraccini 24, Florence, Italy.
Davide
D
Mei
Carla
C
Marini
Francesca
F
Novara
Bernardo D
BD
Bernardina
Tiziana
T
Granata
Elena
E
Fontana
Elena
E
Parrini
Anna R
AR
Ferrari
Alessandra
A
Murgia
Orsetta
O
Zuffardi
Renzo
R
Guerrini
D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics / Q000523:psychology; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D005260:Female; D020440:Gene Duplication; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D015518:Rett Syndrome / Q000175:diagnosis / Q000235:genetics / Q000523:psychology; D013036:Spasms, Infantile / Q000175:diagnosis / Q000235:genetics* / Q000523:psychology; D055815:Young Adult