A Rare Cause of Primary Microcephaly: 4 New Variants in CDK5RAP2 Gene and Review of the Literature

Autosomal recessive primary microcephaly (MCPH) is a rare, genetically heterogeneous disorder characterized by congenital microcephaly, non-progressive intellectual disability, and absence of neurological abnormalities. Pathogenic variants in CDK5RAP2, linked to MCPH3, represent one of the least common causes of MCPH. Autosomal recessive primary microcephaly (MCPH) is a rare, genetically heterogeneous disorder characterized by reduced head size at birth, variable intellectual disability, and no neurological abnormalities. Among This study aimed to identify and characterize novel genetic and clinical findings in patients with CDK5RAP2 gene variants, contributing to the understanding of this rare disorder. Whole exome sequencing (WES) was conducted in 11 patients from five consanguineous families. Six CDK5RAP2 variants were identified, four of which were novel (c.4421del, c.1968G>C, c.3460C>T, c.625dup). Ten patients harbored homozygous variants, whereas one displayed compound heterozygosity. Segregation analysis confirmed carrier status in parents. Clinical evaluations aligned with typical MCPH3 features, though phenotypic variability was observed. This study expands the CDK5RAP2 variant spectrum and reinforces WES as a critical tool for diagnosing rare MCPH subtypes, guiding carrier screening, and improving genetic counseling. The novel variants highlight the genetic diversity underlying MCPH3, urging broader genomic investigations in undiagnosed cases.