Maternal origin of a novel C‐terminal truncation mutation in CDKL5 causing a severe atypical form of Rett syndrome

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Abstract
The CDKL5 gene has been implicated in infantile spasms and more recently in a Rett syndrome‐like phenotype. We report a case of a young girl presenting generalized convulsions at 10 days of life. Subsequent mutation analysis by denaturing high‐performance liquid chromatography of MECP2 and CDKL5 genes revealed heterozygosity for a c.47_48insAGG insertion in exon 1 of MECP2 and heterozygosity for a new nonsense mutation p.Q834X and a new missense variant p.V999M in the CDKL5 gene. Co‐segregation analysis showed that the nonsense mutation was a de novo mutation and that the insertion and the missense variant were also found in the asymptomatic mother. In the absence of skewed X inactivation in the mother, it is likely that these last two variants are not pathogenic. Reverse transcription‐polymerase chain reaction from lymphoblastoid cells of the patient showed only the transcript without the nonsense and missense variations suggesting decreased stability of mature mRNA by nonsense‐mediated decay. These data also suggest an occurrence of the de novo mutation in maternal germ line cells. Moreover, this report reinforces the observation that the CDKL5 phenotype overlaps with Rett syndrome and that CDKL5 gene analysis is recommended in females with a seizure disorder commencing in the first weeks of life.