Validation of a hypomorphic variant in CDK13 as the cause of CHDFIDD with autosomal recessive inheritance through determination of an episignature

Description

Validation of a hypomorphic variant in CDK13 as the cause of CHDFIDD with autosomal recessive inheritance through determination of an episignature Abstract Autosomal dominant CDK13-related disease is characterized by congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD). Heterozygous pathogenic variants, particularly missense variants in the kinase domain, have previously been described as disease causing. Using the determination of a methylation pattern and comparison with an established episignature, we reveal the first hypomorphic variant in the kinase domain of CDK13, leading to a never before described autosomal recessive form of CHDFIDD in a boy with characteristic features. This highlights the utility of episignatures in variant interpretation, as well as a potential novel diagnostic approach in unsolved cases or for disease prognosis. Introduction CDK13-related disorder is an autosomal dominant disease whose acronym, CHDFIDD, is derived from its characteristic features, namely congenital heart defects, dysmorphic facial features, and intellectual developmental delay (MIM #617,360) [, ]. CHDFIDD is the result of heterozygous pathogenic variants in the cyclin dependent kinase 13 (CDK13) gene, which encodes an important transcriptional regulator. It forms functional complexes with Cyclin K (CCNK) and phosphorylates serine residues (specifically Ser2) in the C-terminal domain of RNA polymerase II to alter its transcription of genes, particularly in growth signaling pathways []. CDK13 has a close paralog, CDK12, which also complexes with Cyclin K with comparable, yet not identical, effects on gene transcription [].