Identification of novel CDK19 variants and Drosophila-based in vivo functional evidence supporting pathogenicity in neurodevelopmental disorders.

CDK19

CDK19 variants (Mediator-associated kinase) causing reduced protein stability, aberrant nuclear localization and downregulation of synaptic and neuromuscular genes

CDK19 encodes a Mediator-associated kinase that regulates transcription during neurodevelopment. Twenty-eight individuals with CDK19 variants (12 newly identified, 16 previously reported) were evaluated: all had global developmental delay with prominent speech delay, 67% had epilepsy (most often infantile epileptic spasms syndrome) and 50% hypotonia. Drosophila models showed, for several pathogenic alleles, reduced protein stability, aberrant nuclear localization, tissue toxicity, motor incoordination and allele-specific seizure susceptibility. RNA sequencing of larval brains revealed downregulation of synaptic and neuromuscular genes, which the authors interpret, in an overexpression system, as supportive functional evidence of pathogenicity.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The contribution lies in the 28-person clinical series and in vivo functional data usable as variant-classification evidence, with the authors' own caveat that an overexpression system only counts as support. For exome/genome interpretation, it is the phenotype (speech delay, epilepsy, hypotonia) that helps retain a CDK19 variant. The notion of Mediator complexopathies still needs larger cohorts.

Analysis by Dr Thibaut Benquey