Dissecting the Genetic and Etiological Causes of Primary Microcephaly

Abstract

Autosomal recessive primary microcephaly (MCPH; "small head syndrome") is a rare, heterogeneous disease arising from the decreased production of neurons during brain development. As of August 2020, the Online Mendelian Inheritance in Man (OMIM) database 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 10 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.

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

“…In particular, ARHGEF10 is involved in neuronal morphogenesis and DECIPHER Patient 368323, which carries an ARHGEF10 SNV, presents microcephaly; CSMD1 and KBTBD11 are brain-specific expressed genes, and CSMD1 is also dosage-sensitive. The strict connection between brain genes and microcephaly is well-documented in the literature [ 51 , 52 , 53 ].…”

Altered gene expression and PTSD symptom dimensions in World Trade Center responders

“…Canonically, the COPE protein is the epsilon subunit of the coatomer protein complex I (COPI) which regulates endocytosis from the plasma membrane and is involved in Golgi-to-lysosome transportation. Other subunits of COPI have been implicated in hereditary diseases that cause microcephaly and in autoimmune disorders 63–65 .…”

ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

“…Microcephaly primary hereditary (MCPH) is a rare autosomal recessive genetic disease characterized by neurodevelopmental defects. MCPH can result from mutations in at least 25 genes, while mutations in the abnormal spindle-like microcephaly-associated ( ASPM ) gene ( Bond et al., 2002 ) are the most common cause, representing ~40% of all MCPH cases ( Jean et al., 2020 ). We are among the first to report that (1) both ASPM and microcephalin (MCPH1) are centrosomal/spindle proteins ( Zhong et al., 2005 , 2006 ); (2) both proteins functionally associate with breast cancer type 1 susceptibility protein BRCA1 ( Xu et al., 2004 ; Zhong et al., 2005 ); (3) MCPH1 plays an important role in DNA damage-induced cellular responses ( Xu et al., 2004 ).…”