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Optimizing the molecular diagnosis of CDKL 5 gene–related epileptic encephalopathy in boys
Author(s) -
Mei Davide,
Darra Francesca,
Barba Carmen,
Marini Carla,
Fontana Elena,
Chiti Laura,
Parrini Elena,
Dalla Bernardina Bernardo,
Guerrini Renzo
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12803
Subject(s) - multiplex ligation dependent probe amplification , sanger sequencing , biology , genetics , epilepsy , mutation , encephalopathy , multiplex , medicine , gene , bioinformatics , neuroscience , exon
Summary Objective Mutations involving the cyclin‐dependent kinase‐like 5 ( CDKL 5 ) 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 CDKL 5 in four boys (5.4%) using NGS in one and MLPA in three. Three of four mutations were indicative of somatic mosaicism. Significance CDKL 5 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 CDKL 5 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.