Microcephaly 25, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-25 (MCPH25) is caused by homozygous mutation in the MAP11 gene (618350) on chromosome 7q22. One such family has been reported.

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

Clinical Features

Perez et al. (2019) reported 3 sibs, born of consanguineous Bedouin parents, with primary progressive microcephaly (-5 to -6 SD). The patients were 5, 6, and 7 years of age. Additional features included developmental delay with impaired intellectual development, severe language delay, and severe attention deficit-hyperactivity disorder (ADHD). Some patients had transient short stature with later catch-up growth. Brain imaging showed decreased white matter and a thin corpus callosum; 1 patient had a tethered spinal cord.

Inheritance

The transmission pattern of MCPH25 in the family reported by Perez et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous Bedouin parents, with MCPH25, Perez et al. (2019) identified a homozygous nonsense mutation in the MAP11 gene (E205X; 618350.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient cells suggested that the mutation escaped nonsense-mediated mRNA decay and resulted in the production of a truncated protein.

Animal Model

Perez et al. (2019) generated zebrafish homozygous for map11 knockout or for an map11 loss-of-function mutation. Both mutant lines had reduced neuronal proliferation and smaller head size, recapitulating the human microcephaly phenotype.