Description:
<jats:title>Summary</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Mutations involving the <jats:italic>cyclin‐dependent kinase‐like 5</jats:italic> (<jats:italic><jats:styled-content style="fixed-case">CDKL</jats:styled-content>5</jats:italic>) gene cause an early onset epileptic encephalopathy (<jats:styled-content style="fixed-case">EE</jats:styled-content>) 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 <jats:styled-content style="fixed-case">EE</jats:styled-content> to assess the diagnostic yield of our molecular approach.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We studied 74 boys who presented early onset severe seizures, including infantile spasms and developmental delay, in the setting of <jats:styled-content style="fixed-case">EE</jats:styled-content>, using Sanger sequencing, next‐generation sequencing (<jats:styled-content style="fixed-case">NGS</jats:styled-content>) and multiplex ligation‐dependent probe amplification (<jats:styled-content style="fixed-case">MLPA</jats:styled-content>).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified alterations involving <jats:italic><jats:styled-content style="fixed-case">CDKL</jats:styled-content>5</jats:italic> in four boys (5.4%) using <jats:styled-content style="fixed-case">NGS</jats:styled-content> in one and <jats:styled-content style="fixed-case">MLPA</jats:styled-content> in three. Three of four mutations were indicative of somatic mosaicism.</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p><jats:italic><jats:styled-content style="fixed-case">CDKL</jats:styled-content>5</jats:italic> gene mutations accounted for 5.4% of boys with early onset <jats:styled-content style="fixed-case">EE</jats:styled-content>. 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 <jats:italic><jats:styled-content style="fixed-case">CDKL</jats:styled-content>5</jats:italic> screening remarkably influences the diagnostic yield in boys. Diagnosis is optimized by Sanger sequencing combined with array‐based methods or <jats:styled-content style="fixed-case">MLPA</jats:styled-content>; alternatively, <jats:styled-content style="fixed-case">NGS</jats:styled-content> targeted resequencing designed to also detect copy number alterations, may be performed.</jats:p></jats:sec>