Identification of a novel variant of the CDKl5 gene associated with atypical Rett Syndrome

We present a 4months old female child, with recurrent seizures, staring, jerks, clonic stiffening and posturing. Child has broad prominent forehead , antiverted nares, large eyes, fuller lips and generalized hypotonia . The child had features of atypical Rett syndrome . In changing landscape of disease diagnosis, it is essential to report genotype –phenotype correlations of novel variants where disease modifying therapy is available. Whole Exome sequencing along with mitochondrial genome sequencing was performed on the index patient with in silico predictions and parental segregation. Developmental and epileptic encephalopathy-2 (DEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in impaired intellectual development and poor motor control. We identified a heterozygous variant of uncertain (c.272A>C) in exon 5 of the CDKL5 gene . The population studies indicated the variant as novel and in silico predictions were supportive for disease manifestation . Parental studies indicated that the variant was de novo. Further we correlated evaluated the developmental quotient by Baileys. We identified a novel variant in CDKL5 gene which has some phenotypic overlap with Rett syndrome , but DEE2 is considered to be a distinct entity. Atypical Rett syndrome should be investigated in such cases and just investigating for MECP2 is not enough. Pre clinical trial for CDKL5 Deficiency Disorder (CDD) are available , and thus frequency of different mutation types and genotype-phenotype correlations in CDKL5 Deficiency Disorder (CDD) are of utmost important.
Keywords: Seizures, Atypical Rett syndrome , novel varaint