Microcephaly 12, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-12 (MCPH12) is caused by homozygous mutation in the CDK6 gene (603368) on chromosome 7q21. One such family has been reported.

For a phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Clinical Features

Hussain et al. (2013) reported a highly consanguineous 8-generation Pakistani family in which 10 individuals had primary microcephaly (-4 to -6 SD). All 10 patients had a sloping forehead and mild intellectual disability, but had understandable speech and appropriate social behavior; all could dress independently. None had seizures or other neurologic abnormalities. Brain imaging of 2 patients showed a simplified gyral pattern with no gross structural abnormalities.

Inheritance

The transmission pattern of MCPH12 in the family reported by Hussain et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a large consanguineous Pakistani family with autosomal recessive primary microcephaly, Hussain et al. (2013) found linkage to an 8-cM region on chromosome 7q21.11-q21.3 (maximum multipoint lod score of 10.47).

Molecular Genetics

In affected members of a Pakistani family with MCPH12, Hussain et al. (2013) identified a homozygous missense mutation in the CDK6 gene (A197T; 603368.0001). The mutation, which was found by homozygosity mapping, candidate gene analysis, and whole-exome sequencing, segregated with the disorder in the family. During interphase, patient cells showed normal CDK6 localization, but during mitosis, mutant CDK6 did not localize at the centrosome, the mitotic spindles were disorganized with abnormal microtubule formation, and the nuclei were misshapen. Supernumerary centrosomes were also observed during mitosis. Patient cells showed a reduced growth rate and increased apoptosis compared to controls, as well as impaired motility and polarity. Hussain et al. (2013) postulated a loss-of-function effect of the mutation because the abnormalities observed in patient cells were similar to those observed in in vitro CDK6 knockdown studies. The findings suggested that the mutation affects cell proliferation during neurogenesis.