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

Abstract

CDK20, also known as CCRK, is a cyclin-dependent kinase that regulates cell growth, primary cilium structure, and Sonic Hedgehog signaling. CDK20 has not yet been associated with a known human disorder. In this report, we present a cohort of seven individuals from five unrelated families with bi-allelic variants in CDK20 and an overlapping phenotype of ventriculomegaly or hydrocephalus, midline brain anomalies, abnormal nose, midline cleft lip and/or palate, cryptophthalmos or anophthalmia, postaxial polydactyly, and a sandal toe gap. Immunoblot analysis of fibroblasts derived from two affected fetuses with a homozygous CDK20 c.687+6T>C (p.?) variant demonstrated reduced CDK20 levels. Fibroblasts derived from these affected fetuses were also significantly deficient in cilium formation and function, with abnormal cilium morphology and significantly decreased Hedgehog responsiveness. Our findings support that bi-allelic loss-of-function variants in CDK20 cause a severe ciliopathy with midline brain and facial anomalies.