Microcephaly 14, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-14 (MCPH14) is caused by homozygous mutation in the SASS6 gene (609321) on chromosome 1p21. One such family has been reported.

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

Clinical Features

Khan et al. (2014) reported 4 patients with primary microcephaly from a 5-generation consanguineous Pakistani family. Two affected girls were 6 and 3.5 years of age, and 2 men were 50 and 42 years of age. Head circumference ranged from -6.63 to -19.6 SD, and all had severe mental retardation, impaired speech, and aggressive behavior. The 2 adult patients had seizures, and the 6-year-old girl was unable to walk. CT brain imaging of the 3.5-year-old girl showed a poorly confined basal ganglia, abnormal formation of the lateral ventricles, and hypoplasia of the cerebellar vermis.

Inheritance

The transmission pattern of MCPH14 in the family reported by Khan et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of a consanguineous Pakistani family with primary microcephaly, Khan et al. (2014) identified a homozygous missense mutation in the SASS6 gene (I62T; 609321.0001). The mutation, which was found by a combination of linkage analysis and Sanger sequencing, segregated with the disorder in the family. Transfection of the mutant and wildtype proteins into human cells demonstrated that the I62T mutation impairs the centriole-forming function of SASS6, thus predicting defective cell division. A homozygous missense variant (S219L) in the CAPZA1 gene (601580) also segregated with the disorder, but was not thought to be pathogenic.