P191 – 2505: Two siblings with a CDKL5 mutation: Genotype and phenotype evaluation

Abstract

Objective This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in two sisters. Their phenotype is different despite an identical genotype Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who experience a regression, after an initial normal development. However, CDKL5 patients experience a developmental delay from from birth onwards and seizures starts the first three months of life. Methods Advanced genetic evaluations of the sisters and parents, the electropherogram, clinical and electroencephalographic (EEG) features of both sisters are discussed. Results In the youngest patient, who was known to us prior to appearance of the clinical symptoms, neurological and EEG evaluations at the age of 6 weeks were normal. Infantile spasms evolved at the age of 10 weeks. Simultaneously, she showed a psychomotor regression and deterioration of the EEG into a severe epileptic pattern. Her older sister, was from the start severely hypotonic, had a developmental delay (without regression) and feeding problems and experiences seizures from the age of 8 weeks. In both seizures are refractory. The phenotype of the youngest sister is worse than that of her older sister, despite an identical genotype. This may be explained by differences in X-chromosomal inactivation and other unknown epigenetic and environmental factors. Unfortunately, X inactivation pattern could not be determined in the youngest sister. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Conclusion This report of familial recurrence with suspected germline mosaicism in a healthy parent, has important consequences for genetic counselling. Although it is not possible to predict an exact recurrence risk, it is likely to be increased.