Microcephaly 20, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-20 (MCPH20) is caused by homozygous or compound heterozygous mutation in the KIF14 gene (611279) on chromosome 1q31.

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

Clinical Features

Moawia et al. (2017) reported 9 patients from 4 unrelated families with primary microcephaly. Three of the families (2 Pakistani and 1 Saudi) were consanguineous, and the fourth family (German descent) was nonconsanguineous. In the consanguineous families, patients had microcephaly (-3.6 to -11 SD), moderate to severe intellectual disability, and variable speech impairment. Neuroimaging showed a reduced cerebral cortex with simplified gyral pattern. The patient in German family had a more severe phenotype with microcephaly (-8.6 SD), severe global developmental delay, spastic tetraparesis, no speech, and inability to grip. He also had short stature, small hyperechogenic kidneys, and laboratory evidence of progressive renal impairment. Brain imaging in this child showed a simplified gyral pattern, cerebellar hypoplasia, and absence of the corpus callosum. The mother had a former pregnancy with a similarly affected fetus that was terminated.

Makrythanasis et al. (2018) reported 8 patients from 4 unrelated consanguineous families with MCPH20. Two families were of Egyptian origin, 1 was Turkish, and 1 was Iranian. The severity of the disorder was variable, and microcephaly ranged from the third percentile to -6.4 SD. Two sibs from family 4 were fetuses with severe malformations detected in utero, and the pregnancies were terminated. The other patients ranged in age from 3 to 23 years. They had global developmental delay with variable intellectual disability and poor or absent speech, although some were able to walk. Additional features included strabismus, autistic features, behavioral abnormalities, attention deficit-hyperactivity disorder, aggression, foot deformities, and hypotonia. Two sibs in 1 family (family 2) had short stature, optic nerve hypoplasia, blindness, and microphthalmia. None had genitourinary involvement.

Inheritance

The transmission pattern of MCPH20 in the families reported by Moawia et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 9 patients from 4 unrelated families with MCPH20, Moawia et al. (2017) identified homozygous or compound heterozygous mutations in the KIF14 gene (611279.0003-611279.0007). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient cells showed decreased KIF14 mRNA levels compared to controls. Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. There was only 1 missense mutation that was present in compound heterozygous state with a splice site mutation (611279.0005 and 611279.0006). KIF14 and CRIK (605629) immunoreactivity was not detected at the midbody in patient-derived fibroblasts during cytokinesis. PRC1 (603484) immunoreactivity at the midbody of patient cells was similar to that in controls. Patient-derived fibroblasts from 3 probands showed abnormalities in cytokinesis, with increased numbers of binucleated and apoptotic cells as well as impaired cell migration and motility compared to controls.

In 8 patients from 4 unrelated consanguineous families with MCPH20, Makrythanasis et al. (2018) identified homozygous mutations in the KIF14 gene (see, e.g., 611279.0008 and 611279.0009). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Two of the variants were predicted to result in a frameshift and premature termination, and 2 were missense mutations (G459R and S841F) that occurred in the motor and FHA domains, respectively. Functional studies of the variants and studies of patient cells were not performed, but the authors postulated that the mutations would lead to a defect in cytokinesis.

Animal Model

Fujikura et al. (2013) described a spontaneous mouse mutant, 'laggard' (lag), which was characterized by growth retardation, microcephaly, flat head, and motor impairment. Positional cloning studies showed that the lag mouse resulted from a homozygous splice site mutation in the Kif14 gene, which caused loss of the wildtype protein. Homozygous mutant mice showed progressive severe ataxia, tremors, and muscle weakness, and died within 3 weeks of birth. Neuropathologic examination showed that the brains of mutant mice were small compared to wildtype, with dysgenesis of the cerebral and cerebellar cortices and the hippocampus, and severe hypomyelination of the brain and spinal cord. Gene expression studies showed a dramatic reduction in the expression of genes involved in myelination and maturation of oligodendrocytes. Mutant mice also displayed a dramatic increase in neuronal apoptosis.