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

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

doi:10.1016/j.ejmg.2017.07.017

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

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

Medical Genetics Program

3 Citations (Scopus)

Abstract

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.

Original language	English
Journal	European Journal of Medical Genetics
Volume	60
Issue number	12
Pages (from-to)	627-630
Number of pages	4
ISSN	1769-7212
DOIs	https://doi.org/10.1016/j.ejmg.2017.07.017
Publication status	Published - Dec 2017

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Journal Article

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Abdullah, U., Farooq, M., Mang, Y., Marriam Bakhtiar, S., Fatima, A., Hansen, L., Kjaer, K. W., Larsen, L. A., Faryal, S., Tommerup, N., & Mahmood Baig, S. (2017). A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous Pakistani family. European Journal of Medical Genetics, 60(12), 627-630. https://doi.org/10.1016/j.ejmg.2017.07.017

Abdullah, U, Farooq, M , Mang, Y, Marriam Bakhtiar, S, Fatima, A, Hansen, L , Kjaer, KW , Larsen, LA, Faryal, S, Tommerup, N & Mahmood Baig, S 2017, 'A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous Pakistani family', European Journal of Medical Genetics, vol. 60, no. 12, pp. 627-630. https://doi.org/10.1016/j.ejmg.2017.07.017

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

abstract = "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.",

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author = "Uzma Abdullah and Muhammad Farooq and Yuan Mang and {Marriam Bakhtiar}, Syeda and Ambrin Fatima and Lars Hansen and Kjaer, {Klaus Wilbrandt} and Larsen, {Lars Allan} and Sanam Faryal and Niels Tommerup and {Mahmood Baig}, Shahid",

year = "2017",

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doi = "10.1016/j.ejmg.2017.07.017",

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T1 - A novel mutation in CDK5RAP2 gene causes primary microcephaly with speech impairment and sparse eyebrows in a consanguineous Pakistani family

AU - Abdullah, Uzma

AU - Farooq, Muhammad

AU - Mang, Yuan

AU - Marriam Bakhtiar, Syeda

AU - Fatima, Ambrin

AU - Hansen, Lars

AU - Kjaer, Klaus Wilbrandt

AU - Larsen, Lars Allan

AU - Faryal, Sanam

AU - Tommerup, Niels

AU - Mahmood Baig, Shahid

PY - 2017/12

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N2 - 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.

AB - 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.

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DO - 10.1016/j.ejmg.2017.07.017

M3 - Journal article

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SN - 1769-7212

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SP - 627

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JO - European Journal of Medical Genetics

JF - European Journal of Medical Genetics

IS - 12

ER -

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

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