Optimizing the molecular diagnosis of CDKL5 gene-related epileptic encephalopathy in boys.
OBJECTIVE
Mutations involving the cyclin-dependent kinase-like 5 (CDKL5) gene cause an early onset epileptic encephalopathy (EE) with severe neurologic impairment and a skewed 12:1 female-to-male ratio. To date, 18 mutations have been described in boys. We analyzed our cohort of boys with early onset EE to assess the diagnostic yield of our molecular approach.


METHODS
We studied 74 boys who presented early onset severe seizures, including infantile spasms and developmental delay, in the setting of EE, using Sanger sequencing, next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA).


RESULTS
We identified alterations involving CDKL5 in four boys (5.4%) using NGS in one and MLPA in three. Three of four mutations were indicative of somatic mosaicism.


SIGNIFICANCE
CDKL5 gene mutations accounted for 5.4% of boys with early onset EE. Somatic mosaic mutations might be even more represented than germline mutations, probably because their less deleterious effect enhances viability of the male embryo. The molecular approach used for CDKL5 screening remarkably influences the diagnostic yield in boys. Diagnosis is optimized by Sanger sequencing combined with array-based methods or MLPA; alternatively, NGS targeted resequencing designed to also detect copy number alterations, may be performed.
['Mei|Davide|D|', 'Darra|Francesca|F|', 'Barba|Carmen|C|', 'Marini|Carla|C|', 'Fontana|Elena|E|', 'Chiti|Laura|L|', 'Parrini|Elena|E|', 'Dalla Bernardina|Bernardo|B|', 'Guerrini|Renzo|R|']
D000293:Adolescent D002648:Child D002675:Child, Preschool D002658:Developmental Disabilities D004827:Epilepsy D020022:Genetic Predisposition to Disease D059014:High-Throughput Nucleotide Sequencing D006801:Humans D007223:Infant D008297:Male D009154:Mutation D017346:Protein Serine-Threonine Kinases D015518:Rett Syndrome
CDKL5 Epileptic encephalopathy Mutation Mosaic