Bi-allelic variants in CDK20 cause a severe ciliopathy with midline brain and facial anomalies.

Bi-allelic loss-of-function CDK20 (CCRK) variants impairing ciliogenesis and Sonic Hedgehog signalling

CDK20 (also known as CCRK), a cyclin-dependent kinase regulating primary cilium structure and Sonic Hedgehog signalling, had not previously been linked to any human disorder. This study describes seven individuals from five unrelated families with bi-allelic CDK20 variants sharing an overlapping phenotype: ventriculomegaly or hydrocephalus, midline brain anomalies, midline cleft lip/palate, cryptophthalmos or anophthalmia, postaxial polydactyly and a sandal toe gap. Fibroblasts from two homozygous fetuses (c.687+6T>C) showed reduced CDK20, defective ciliogenesis with abnormal cilium morphology, and decreased Hedgehog responsiveness. The authors conclude that bi-allelic loss-of-function of CDK20 causes a severe ciliopathy with midline brain and facial anomalies.

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

A robust first report combining a multi-family cohort with direct functional evidence (ciliogenesis, Hedgehog signalling) — the expected standard for establishing a new Mendelian gene. CDK20 is already captured by WES/WGS: the priority now is its annotation in the interpretation of fetal ciliopathies and midline syndromes, and its inclusion in the differential diagnosis of Meckel- or oral-facial-digital-type presentations.

Analysis by Dr Thibaut Benquey