ORPHA: 2512; DO: 0070292;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q21.1 | Microcephaly 9, primary, autosomal recessive | 614852 | Autosomal recessive | 3 | CEP152 | 613529 |
A number sign (#) is used with this entry because autosomal recessive primary microcephaly-9 (MCPH9) is caused by homozygous or compound heterozygous mutation in the CEP152 gene (613529) on chromosome 15q21.
Primary microcephaly (MCPH) is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations below the age- and sex-matched population mean and impaired intellectual development, with no other associated malformations and with no apparent etiology. Most cases of primary microcephaly show an autosomal recessive mode of inheritance (Woods et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Guernsey et al. (2010) reported 3 unrelated patients from eastern Canada with primary microcephaly. In all families, both parents were of Acadian descent. All patients had head circumferences between 5 and 7 standard deviations below the mean, and none had other dysmorphic features. In infancy, all were noted to have fast, jerky movements, as well as mirror movements. There was mild psychomotor delay. The patients were friendly, happy, socially aware, and attended school, although there were some behavioral disorders, such as impulsivity, aggression, and tantrums. One had tics, and another had obsessive-compulsive traits. Psychologic testing of 1 patient showed moderate cognitive impairment. None had epilepsy. Brain MRI of 1 patient showed markedly reduced brain size and simplified gyral pattern.
Sajid Hussain et al. (2013) reported 2 members of a consanguineous Pakistani family with severe microcephaly (-11 to -13 SD) at the ages of 10 to 24 years. The patients could speak complete sentences and had self-care skills, but showed self-injurious behaviors.
By genomewide linkage analysis followed by candidate gene sequencing of 3 unrelated patients from eastern Canada with primary microcephaly, Guernsey et al. (2010) identified homozygous or compound heterozygous mutations in the CEP152 gene (613529.0001-613529.0002) on chromosome 15q21.
In 2 members of a consanguineous Pakistani family (MCP43) with MCPH9, Sajid Hussain et al. (2013) identified 2 in cis homozygous mutations in the CEP152 allele (613529.0008). The mutations, which were found by linkage analysis followed by Sanger sequencing of the candidate gene, segregated with the disorder in the family. The family was ascertained from a larger cohort of 57 consanguineous Pakistani families with autosomal recessive microcephaly who underwent linkage analysis to known MCPH loci. Three families showed linkage to CEP152, but mutations were only identified in 1 family.
Although mutation in the CEP152 gene on chromosome 15q21 was thought to cause MCPH4 (604321) based on the report of Guernsey et al. (2010), Genin et al. (2012) later identified a mutation in the CASC5 gene on 15q14 in the original family with MCPH4 (Jamieson et al., 1999). Microcephaly caused by mutation in the CEP152 gene is now designated MCPH9, and microcephaly caused by mutation in the CASC5 gene is now designated MCPH4.
Genin, A., Desir, J., Lambert, N., Biervliet, M., Van Der Aa, N., Pierquin, G., Killian, A., Tosi, M., Urbina, M., Lefort, A., Libert, F., Pirson, I., Abramowicz, M. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum. Molec. Genet. 21: 5306-5317, 2012. [PubMed: 22983954] [Full Text: https://doi.org/10.1093/hmg/dds386]
Guernsey, D. L., Jiang, H., Hussin, J., Arnold, M., Bouyakdan, K., Perry, S., Babineau-Sturk, T., Beis, J., Dumas, N., Evans, S. C., Ferguson, M., Matsuoka, M., and 12 others. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am. J. Hum. Genet. 87: 40-51, 2010. [PubMed: 20598275] [Full Text: https://doi.org/10.1016/j.ajhg.2010.06.003]
Jamieson, C. R., Govaerts, C., Abramowicz, M. J. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. (Letter) Am. J. Hum. Genet. 65: 1465-1469, 1999. [PubMed: 10521316] [Full Text: https://doi.org/10.1086/302640]
Sajid Hussain, M., Marriam Bakhtiar, S., Farooq, M., Anjum, I., Janzen, E., Reza Toliat, M., Eiberg, H., Kjaer, K. W., Tommerup, N., Noegel, A. A., Nurnberg, P., Baig, S. M., Hansen, L. Genetic heterogeneity in Pakistani microcephaly families. Clin. Genet. 83: 446-451, 2013. [PubMed: 22775483] [Full Text: https://doi.org/10.1111/j.1399-0004.2012.01932.x]
Woods, C. G., Bond, J., Enard, W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am. J. Hum. Genet. 76: 717-728, 2005. [PubMed: 15806441] [Full Text: https://doi.org/10.1086/429930]