Mutations in CDK 5 RAP 2 cause Seckel syndrome

Seckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice‐site mutations c.383+1G>C and c.4005‐9A>G in CDK 5 RAP 2 in two consanguineous families with Seckel syndrome. CDK 5 RAP 2 ( CEP 215) encodes a centrosomal protein which is known to be essential for centrosomal cohesion and proper spindle formation and has been shown to be causally involved in autosomal recessive primary microcephaly. We establish CDK 5 RAP 2 as a disease‐causing gene for Seckel syndrome and show that loss of functional CDK 5 RAP 2 leads to severe defects in mitosis and spindle organization, resulting in cells with abnormal nuclei and centrosomal pattern, which underlines the important role of centrosomal and mitotic proteins in the pathogenesis of the disease. Additionally, we present an intriguing case of possible digenic inheritance in Seckel syndrome: A severely affected child of nonconsanguineous German parents was found to carry heterozygous mutations in CDK 5 RAP 2 and CEP 152 . This finding points toward a potential additive genetic effect of mutations in CDK 5 RAP 2 and CEP 152 .