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In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development., (Copyright © 2017 American Society of Human Genetics. All rights reserved.)

DNA copy number alterations in 15q24 have repeatedly been reported in patients exhibiting mild to moderate developmental delay and dysmorphic features. To date, mainly microdeletions have been described, and comparison of overlapping regions allowed the definition of minimal critical regions (MCRs) for microdeletions as well as microduplications. These MCRs are associated with distinct phenotypes. Recently, a family with a new microduplication distal to these MCRs was reported. However, for this alteration the typical phenotypical consequences could not yet be determined. Here we present another family with a nearly identical microduplication exhibiting a broad clinical spectrum including developmental delay, autistic traits and dysmorphic features. Our data suggest that microduplications adjacent and distal to the known MCRs are variable in expressivity and are associated with distinct features. They might represent a novel and recurrent microduplication syndrome., (© 2010 Wiley-Liss, Inc.)