A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous Pakistani family

作者：Abdullah Uzma; Farooq Muhammad^*; Mang Yuan; Bakhtiar Syeda Marriam; Fatima Ambrin; Hansen Lars; Kjaer Klaus Wilbrandt; Larsen Lars Allan; Faryal Sanam; Tommerup Niels; Baig Shahid Mahmood^*

来源：European Journal of Medical Genetics, 2017, 60(12): 627-630.

DOI：10.1016/j.ejmg.2017.07.017

• CDK5RAP2
• Exome
• Microcephaly
• Speech impairment
• Pakistani

CDK5RAP2 gene encodes a centrosomal protein, highly expressed in fetal brain and essentially indispensable for its normal development, as biallelic mutations in it lead to primary microcephaly (MCPH). Despite being known as MCPH linked gene for more than a decade, the phenotypic spectrum of CDK5RAP2 mutations is still under explored as only eleven families have been reported worldwide. Here, we analyzed a consanguineous Pakistani MCPH family, characterized by moderate to severe intellectual disability, speech impairment, moderately short stature and sparse eyebrows. Whole exome sequencing of the proband identified a 2bp duplication in exon 34 of CDK5RAP2 that causes frame- shift, leading to a premature stop codon. The resultant transcript is resistant to nonsense mediated decay, suggesting that the mutation leads to a truncated protein lacking C-terminal domains; CDK5R1, and Cnn motif 2 (CM2), required for its localization to centrosome and Golgi Apparatus. Clinical variability observed in the family highlights the importance of further detailed clinical description of patients with CDK5RAP2 mutations.

• 出版日期2017-12