AUTHOR=Jean Francesca , Stuart Amanda , Tarailo-Graovac Maja 

TITLE=Dissecting the Genetic and Etiological Causes of Primary Microcephaly

JOURNAL=Frontiers in Neurology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2020.570830

DOI=10.3389/fneur.2020.570830

ISSN=1664-2295

ABSTRACT=Autosomal recessive primary microcephaly (MCPH; “small head syndrome”) is a rare, heterogenous disease arising from the decreased production of neurons during brain development. As of August 2020, OMIM lists 25 genes (involved in molecular processes such as centriole biogenesis, microtubule dynamics, spindle positioning, DNA repair, transcriptional regulation, Wnt signaling, and cell cycle checkpoints) that are implicated in causing MCPH. Many of these 25 genes were only discovered in the last ten years following advances in exome and genome sequencing that have improved our ability to identify disease-causing variants. Despite these advances, many patients still lack a genetic diagnosis. This demonstrates a need to understand in greater detail the molecular mechanisms and genetics underlying MCPH. Here, we briefly review the molecular functions of each MCPH gene and how their loss disrupts the neurogenesis program, ultimately demonstrating that microcephaly arises from cell cycle dysregulation. We also explore the current issues in the genetic basis and clinical presentation of MCPH as additional avenues of improving gene/variant prioritization. Ultimately, we illustrate that the detailed exploration of the etiology and inheritance of MCPH improves the predictive power in identifying previously unknown MCPH candidates and diagnosing microcephalic patients.