Novel biallelic CDK9 variants are associated with retinal dystrophy without CHARGE-like malformation syndrome

Cyclin-dependent kinase 9 (CDK9) phosphorylates the C-terminal domain of RNA polymerase II (RNAPII) to regulate transcription. Previously, we reported that an 8-year-old boy with the biallelic CDK9 variants p.A288T and p.R303C exhibited a CHARGE-like malformation syndrome in which retinal dystrophy was a distinguishing feature. This dystrophy was caused by the decreased CDK9 kinase activity associated with these variant alleles [wild-type (WT) > A288T > R303C]. In this study, we describe a female patient who also bears biallelic CDK9 variants but displays retinal dystrophy without a CHARGE-like malformation syndrome. Trio-based whole-exome sequencing identified a new variant CDK9 allele, p.P321S, that occurred de novo in the patient. As a result, this female patient displayed compound heterozygous variants composed of the p.A288T CDK9 variant of maternal origin plus the novel p.P321S variant. With respect to reduced kinase activity, the new variant could be ranked as WT > P321S > A288T. Thus, our study raises a possibility that retinal dystrophy can arise with or without a CHARGE-like malformation syndrome depending on the level of kinase activity associated with the combination of variant CDK9 alleles present.