ORPHA: 2512; DO: 0070290;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q12.12-q12.13 | Microcephaly 6, primary, autosomal recessive | 608393 | Autosomal recessive | 3 | CENPJ | 609279 |
A number sign (#) is used with this entry because of evidence that primary microcephaly-6 (MCPH6) is caused by homozygous mutation in the gene encoding centromeric protein J (CENPJ; 609279) on chromosome 13q12.
For a phenotypic description and discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).
Darvish et al. (2010) reported 2 affected individuals from a consanguineous Iranian family with autosomal recessive primary microcephaly. In addition to severe mental retardation and microcephaly (-4 to -6 SD), the patients had additional features, including small ears, hypertelorism, strabismus, notched nasal tip, seizures, joint stiffness, and wheelchair requirement.
Sajid Hussain et al. (2013) reported 10 patients from 3 consanguineous Pakistani families with primary microcephaly (-8 to -17 SD) between ages 7 and 30 years. Most of the patients were unable to speak or write.
The transmission pattern of MCPH6 in the families reported by Darvish et al. (2010) and Sajid Hussain et al. (2013) was consistent with autosomal recessive inheritance.
Leal et al. (2003) reported a novel locus, MCPH6, for autosomal recessive primary microcephaly, mapping to 13q12.2, in a Brazilian family. The minimal critical regions spanned 6 Mb between 2 markers with a maximum 2-point lod score of 6.25.
By homozygosity mapping, Darvish et al. (2010) found linkage to the MCPH6 locus in 5 of 112 consanguineous Iranian families with primary microcephaly.
In affected members of 3 families with MCPH6, of which 1 was the Brazilian family previously described by Leal et al. (2003) and 2 were Pakistani, Bond et al. (2005) identified a homozygous mutation in the CENPJ gene (609279.0001-609279.0002, respectively). Each mutation was absent from 380 northern Pakistani control chromosomes, showed the expected disease segregation in families, and was not present in chimpanzee, gorilla, orangutan, gibbon, mouse, or rat.
In affected members of a Pakistani family with MCPH6, Gul et al. (2006) identified homozygosity for a 4-bp deletion in the CENPJ gene (609279.0003).
In 2 affected members of a consanguineous Iranian family with primary microcephaly, Darvish et al. (2010) identified a homozygous mutation in the CENPJ gene (T821M; 609279.0005).
In 10 patients from 3 consanguineous Pakistani families with MCPH6, Sajid Hussain et al. (2013) identified a homozygous truncating mutation in the CENPJ gene (609279.0001). The mutations, which were found by linkage analysis followed by Sanger sequencing of the candidate gene, segregated with the disorder in the families. The families were ascertained from a larger cohort of 57 consanguineous Pakistani families with autosomal recessive microcephaly who underwent linkage analysis to known MCPH loci.
Bond, J., Roberts, E., Springell, K., Lizarraga, S., Scott, S., Higgins, J., Hampshire, D. J., Morrison, E. E., Leal, G. F., Silva, E. O., Costa, S. M. R., Baralle, D., Raponi, M., Karbani, G., Rashid, Y., Jafri, H., Bennett, C., Corry, P., Walsh, C. A., Woods, C. G. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nature Genet. 37: 353-355, 2005. Note: Erratum: Nature Genet. 37: 555 only, 2005. [PubMed: 15793586] [Full Text: https://doi.org/10.1038/ng1539]
Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. A clinical and molecular genetic study of 112 Iranian families with primary microcephaly. J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014. [PubMed: 20978018] [Full Text: https://doi.org/10.1136/jmg.2009.076398]
Gul, A., Hassan, M. J., Hussain, S., Raza, S. I., Chishti, M. S., Ahmad, W. A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly. J. Hum. Genet. 51: 760-764, 2006. [PubMed: 16900296] [Full Text: https://doi.org/10.1007/s10038-006-0017-1]
Leal, G. F., Roberts, E., Silva, E. O., Costa, S. M. R., Hampshire, D. J., Woods, C. G. A novel locus for autosomal recessive primary microcephaly (MCPH6) maps to 13q12.2. J. Med. Genet. 40: 540-542, 2003. [PubMed: 12843329] [Full Text: https://doi.org/10.1136/jmg.40.7.540]
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]