Microcephaly 13, Primary, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-13 (MCPH13) is caused by compound heterozygous mutation in the CENPE gene (117143) on chromosome 4q24. One such family has been reported.

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

Clinical Features

Mirzaa et al. (2014) reported a brother and sister, born of unrelated parents of European descent, with microcephaly, poor overall growth, and developmental delay. Both had intrauterine growth retardation and microcephaly apparent on prenatal ultrasound, as well as similar dysmorphic facial features, including sloping forehead, prominent nose, and mild micrognathia. At age 5 years, the older sib, a boy, had microcephaly (-9 SD), short stature (-7 SD), small hands and feet, mild spasticity, and severely delayed psychomotor development with absent speech and poor gross and fine motor skills. Brain imaging at age 17 days showed a diffuse, severely simplified gyral pattern with partial agenesis of the corpus callosum and cerebellar hypoplasia. Skeletal survey showed subtle widening of the ribs and possible metaphyseal areas of sclerosis in the distal femurs and proximal tibias. The hands appeared osteopenic, and the metacarpals were relatively short. There was no craniosynostosis. Mirzaa et al. (2014) noted that the skeletal findings were not characteristic of a specific bone dysplasia, particularly not of microcephalic osteodysplastic primordial dwarfism-2 (MOPD2; 210720), but suggested that those features may become more apparent with age. Additional features in the boy included well-controlled infantile seizures and congenital restrictive cardiomyopathy, which were not found in his affected sister. He died of pneumonia at age 8 years. At age 3 years, the sister had microcephaly (-7 SD) and mild short stature (-2 to -3 SD), as well as delayed psychomotor development, which was not as severe as that in her brother. Brain imaging and skeletal survey of the sister were apparently not performed. Mirzaa et al. (2014) concluded that the phenotype was part of the spectrum that includes primary microcephaly and microcephalic primordial dwarfism.

Inheritance

The transmission pattern of MCPH13 in the family reported by Mirzaa et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a brother and sister, born of unrelated parents of European descent, with autosomal recessive primary microcephaly-13, Mirzaa et al. (2014) identified compound heterozygous missense mutations in the CENPE gene (D933N, 117143.0001 and K1355E, 117143.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Studies of patient cells and cells transfected with the mutations demonstrated abnormalities in spindle microtubule organization and mitotic progression.