Modifier genes in microcephaly: A report on WDR62, CEP63, RAD50 and PCNT variants exacerbating disease caused by biallelic mutations of ASPM and CENPJ

Authors

Ehtisham Ul Haq Makhdoom, University of Cologne, Cologne, Germany
Syeda Seema Waseem, University of Cologne, Cologne, Germany
Maria Iqbal, University of Cologne, Cologne, Germany
Uzma Abdullah, PMAS-Arid Agriculture University, Rawalpindi, Pakistan
Ghulam Hussain, Government College University, Faisalabad, Pakistan
Maria Asif, University of Cologne, Cologne, Germany
Birgit Budde, University of Cologne, Cologne, Germany
Wolfgang Höhne, University of Cologne, Cologne, Germany
Ambrin Fatima, Aga Khan UniversityFollow
Shahid Mahmood Baig, Aga Khan UniversityFollow

Document Type

Article

Department

Biological and Biomedical Sciences

Abstract

Congenital microcephaly is the clinical presentation of significantly reduced head circumference at birth. It manifests as both non-syndromic-microcephaly primary hereditary (MCPH)-and syndromic forms and shows considerable inter- and intrafamilial variability. It has been hypothesized that additional genetic variants may be responsible for this variability, but data are sparse. We have conducted deep phenotyping and genotyping of five Pakistani multiplex families with either MCPH (n = 3) or Seckel syndrome (n = 2). In addition to homozygous causal variants in ASPM or CENPJ, we discovered additional heterozygous modifier variants in WDR62, CEP63, RAD50 and PCNT-genes already known to be associated with neurological disorders. MCPH patients carrying an additional heterozygous modifier variant showed more severe phenotypic features. Likewise, the phenotype of Seckel syndrome caused by a novel CENPJ variant was aggravated to microcephalic osteodysplastic primordial dwarfism type II (MOPDII) in conjunction with an additional PCNT variant. We show that the CENPJ missense variant impairs splicing and decreases protein expression. We also observed centrosome amplification errors in patient cells, which were twofold higher in MOPDII as compared to Seckel cells. Taken together, these observations advocate for consideration of additional variants in related genes for their role in modifying the expressivity of the phenotype and need to be considered in genetic counseling and risk assessment.

Comments

Pagination are not provided by the author/publisher

Publication (Name of Journal)

Genes

Recommended Citation

Makhdoom, E., Waseem, S. S., Iqbal, M., Abdullah, U., Hussain, G., Asif, M., Budde, B., Höhne, W., Fatima, A., Baig, S. M. (2021). Modifier genes in microcephaly: A report on WDR62, CEP63, RAD50 and PCNT variants exacerbating disease caused by biallelic mutations of ASPM and CENPJ. Genes, 12(5), 731.
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_bbs/946

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