TABLE 1.
Genes frequently mutated in primary microcephaly that plays roles in cell cycle regulation, centrosome/cilium formation, spindle orientation, microtubule organization and impaired DNA damage.
| Genes | Syndrome | Subcellular localization | Modeled in patient specific brain organoids | Mechanisms revealed | References |
| MCPH1 | Congenital microcephaly | Nucleus | No | Premature NPCs differentiation, premature chromosome condensation | Jackson et al., 2002; Passemard et al., 2011; Zhou et al., 2013; Farooq et al., 2016 |
| ASPM | Congenital microcephaly | Centrosomes | Yes | Decreased NPCs proliferation, Less neuronal activity, cell death | Pulvers et al., 2010; Fujimori et al., 2014 |
| WDR62 | Congenital microcephaly, cortical abnormalities | Centrosomes | No | Decreased NPCs proliferation, premature NPCs differentiation | Nicholas et al., 2010; Shohayeb et al., 2019; Zhang et al., 2019 |
| CDK5RAP2 | Congenital microcephaly | Centrosomes | Yes | Decreased NPCs proliferation, premature NPCs differentiation | Bond et al., 2005; Barrera et al., 2010; Buchman et al., 2010; Babrowski et al., 2013 |
| CENPJ/CPAP | Congenital microcephaly, Seckel syndrome | Centrosomes | Yes | Decreased NPCs proliferation premature NPCs differentiation | Al-Dosari et al., 2010; McIntyre et al., 2012; Alcantara and O’Driscoll, 2014; Aldape et al., 2019 |
| SAS6 | Congenital microcephaly | Centrosomes | No | Decreased NPCs proliferation | Khan et al., 2014; Tang et al., 2016 |
| STIL | Congenital microcephaly | Centrosomes | No | Neural tube defects | Consortium et al., 2009; Amartely et al., 2014 |
| CEP152 | Congenital microcephaly, Seckel syndrome | Centrosomes | No | Decreased NPCs proliferation | Guernsey et al., 2010; Kalay et al., 2011 |
| CEP63 | Seckel syndrome | Centrosomes | No | Increased neuronal death, increased mitotic error | Alcantara and O’Driscoll, 2014; Marjanovic et al., 2015 |
| NDE1 | Congenital microcephaly, | Centrosomes and spindle microtubules | No | Decreased NPCs proliferation | Alcantara and O’Driscoll, 2014; Baffet et al., 2016 |
| PCNT | Congenital microcephaly, Seckel syndrome, MOPD type II |
Centrosomes | No | Decreased NPCs proliferation, aberrant mitosis, missegregation of chromosomes | Griffith et al., 2008; Miyoshi et al., 2009; Benmerah et al., 2015 |
| RTTN | Congenital microcephaly, dwarfism, cerebellar abnormalities | Centrosomes | No | Abnormal spindles, centriole structures | Shamseldin et al., 2015; Chen et al., 2017 |
| KIF5C | Cortical dysplasia | Spindles | No | Abnormal microtubule function | Poirier et al., 2013 |
| KIF2A | Cortical dysplasia | Spindles | No | Abnormal axon branching, abnormal microtubule function | Poirier et al., 2013 |
| KIF11 | Congenital microcephaly | Centrosomes, spindle, and cilia | No | Abnormal spindles and reduced NPCs proliferation | Ostergaard et al., 2012 |
| KIF14 | Congenital microcephaly, Meckel syndrome | Centrosomes, spindle | No | Increased neuronal cell death, abnormal cell migration | Moawia et al., 2017 |
| TUBA1A | Cortical abnormalities, tubulinopathy | Variable, microtubule | No | Abnormal neuronal migration | Wei et al., 2019 |
| TUBG1 | Cortical abnormalities, tubulinopathy | Variable, microtubule | No | Abnormal neuronal migration | Poirier et al., 2013 |
| TUBB2B | Cortical abnormalities, tubulinopathy | Variable, microtubule | No | Abnormal neuronal migration | Romaniello et al., 2012 |
| CEP135 | Congenital microcephaly | Centrosomes | No | Abnormal centriole structures, disorganized spindles, reduced NPCs proliferation | Hussain et al., 2012; Lin et al., 2013 |
| CDK6 | Congenital microcephaly | Centrosomes | No | Abnormal spindle, unknown mechanisms | Hussain et al., 2013 |
| CIT | Congenital microcephaly, dwarfism | Mid body | No | Mitotic delay, impaired cytokinesis, multipolar spindles, genomic instability, cell death | Li et al., 2016; Shaheen et al., 2016 |
| Ninein | Seckel syndrome | Centrosomes | No | Defective migration, neuroectoderm defects | Dauber et al., 2012 |
| NBS1 | Congenital microcephaly, Nijmegen breakage syndrome | Nucleus | No | Double strand break repair deficiency | Varon et al., 1998 |
| ATR | Seckel syndrome | Nucleus | No | Mitotic delay, impaired cytokinesis, double strand break repair deficiency | O’Driscoll et al., 2003 |
| XLF/Cernunos | Congenital microcephaly | Nucleus | No | Double strand break repair deficiency | Buck et al., 2006 |
| XRCC2 | Congenital microcephaly | Nucleus | No | Double strand break repair deficiency neuronal death | Deans et al., 2000 |
| XRCC4 | Congenital microcephaly | Nucleus | No | Double strand break repair deficiency neuronal death | Gao et al., 1998 |
| Ligase IV deficiency | Congenital microcephaly | Nucleus variable | No | Double strand break repair deficiency | Barnes et al., 1998 |
| XPA-XPG | Xeroderma Pigmentosum, Microcephaly, Variable | Nucleus variable | No | Double strand break repair deficiency | Anttinen et al., 2008 |
| ERCC6, ERCC8 | Cockayne Syndrome microcephaly | Nucleus variable | No | Nucleotide excision repair and base excision repair deficiency | Jackson et al., 2002; Lin et al., 2005 |
| TTDA | Congenital microcephaly | Nucleus variable | No | Double strand break repair deficiency | Chu and Mayne, 1996; Faghri et al., 2008 |
| DNAPK | Congenital microcephaly, Seizures, Neuronal death | Nucleus variable | No | Double strand break repair deficiency | Vemuri et al., 2001 |