ORPHA: 2512; DO: 0070282;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q12 | Microcephaly 8, primary, autosomal recessive | 614673 | Autosomal recessive | 3 | CEP135 | 611423 |
A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-8 (MCPH8) is caused by homozygous mutation in the CEP135 gene (611423) on chromosome 4q.
For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Hussain et al. (2012) reported 2 sibs, born of consanguineous Pakistani parents, with primary microcephaly apparent at birth. Each had a sloping forehead, retrognathia, severe cognitive deficits, and unintelligible speech at age 5 years. One died at age 11 years. The head circumferences ranged between -12 and -14.5 SD. No other abnormalities were noted.
Farooq et al. (2016) reported 2 sibs, born of consanguineous Pakistani parents, with MCPH8. The patients had severe learning disabilities and speech impairment, but no seizures. Their head circumferences at the age of 10 and 7 years were -14 and -12 SD, respectively.
The transmission pattern of primary microcephaly in the family reported by Hussain et al. (2012) was consistent with autosomal recessive inheritance.
In 2 sibs, born of consanguineous Pakistani parents, with autosomal recessive primary microcephaly-8, Hussain et al. (2012) identified a homozygous truncating mutation in the CEP135 gene (611423.0001). The mutation was identified by genomewide linkage analysis followed by candidate gene sequencing, and was not found in 384 Pakistani controls. Whole-exome sequencing of 1 of the patients did not identify other potentially pathogenic mutations that could be responsible for the disorder. The parents were healthy with normal head circumference; the father carried the mutation in heterozygous state. Cultured patient fibroblasts showed poor growth and had increased numbers of fragmented centrosomes per cell compared to controls. The microtubule network was frequently disorganized (55% of the cells) and showed cell shape changes as well as misshapen and fragmented nuclei. Approximately 22% of mutant patient fibroblasts were without centrosomes, which was never observed in control cells. In vitro functional expression studies of the mutant protein in COS-7 cells caused abnormal disorganized microtubule networks, and the mutant protein did not localize to the centrosome. The findings indicated that CEP135 is an essential component of the centrosome.
In 2 sibs, born of consanguineous Pakistani parents, with MCPH8, Farooq et al. (2016) identified a homozygous splice site mutation in the CEP135 gene (611423.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was predicted to result in nonsense-mediated mRNA decay, but if translated, the mutant protein would lack the C-terminal hSAS-6 interacting domain and would most likely result in multiple and fragmented centrosomes with disorganized microtubules.
Farooq, M., Fatima, A., Mang, Y., Hansen, L., Kjaer, K. W., Baig, S. M., Larsen, L. A., Tommerup, N. A novel splice site mutation in CEP135 is associated with primary microcephaly in a Pakistani family. J. Hum. Genet. 61: 271-273, 2016. [PubMed: 26657937] [Full Text: https://doi.org/10.1038/jhg.2015.138]
Hussain, M. S., Baig, S. M., Neumann, S., Nurnberg, G., Farooq, M., Ahmad, I., Alef, T., Hennies, H. C., Technau, M., Altmuller, J., Frommolt, P., Thiele, H., Noegel, A. A., Nurnberg, P. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am. J. Hum. Genet. 90: 871-878, 2012. [PubMed: 22521416] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.016]