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Annu Rev Genomics Hum Genet. 2018 Aug 31;19:177-200. doi: 10.1146/annurev-genom-083117-021441. Epub 2018 May 23.

The Genetics of Primary Microcephaly.

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Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
Harvard-MIT MD-PhD Program, Harvard Medical School, Boston, Massachusetts 02115, USA.
Current affiliation: Boston Combined Residency Program (Child Neurology), Boston Children's Hospital, Boston, Massachusetts 02115, USA; email:
Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA; email:
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Departments of Pediatrics and Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA; email:


Primary microcephaly (MCPH, for "microcephaly primary hereditary") is a disorder of brain development that results in a head circumference more than 3 standard deviations below the mean for age and gender. It has a wide variety of causes, including toxic exposures, in utero infections, and metabolic conditions. While the genetic microcephaly syndromes are relatively rare, studying these syndromes can reveal molecular mechanisms that are critical in the regulation of neural progenitor cells, brain size, and human brain evolution. Many of the causative genes for MCPH encode centrosomal proteins involved in centriole biogenesis. However, other MCPH genes fall under different mechanistic categories, notably DNA replication and repair. Recent gene discoveries and functional studies have implicated novel cellular processes, such as cytokinesis, centromere and kinetochore function, transmembrane or intracellular transport, Wnt signaling, and autophagy, as well as the apical polarity complex. Thus, MCPH genes implicate a wide variety of molecular and cellular mechanisms in the regulation of cerebral cortical size during development.


DNA repair; centrosome; microcephaly; radial glial cells

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