Skip to main content
. 2018 Dec;20(4):267–282. doi: 10.31887/DCNS.2018.20.4/gmirzaa

TABLE I. Pathways and genes underlying microcephaly (MIC) and megalencephaly (MEG).

Pathway/cell function Genes Inheritance Neuronal phenotype Brain MRI findings Syndromic association Body growth abnormalities Cancer predisposition* Epilepsy
MICROCEPHALY
Cell cycle: Centro-some formation, spindle orientation, microtubule organization, cytokinesis MCPH1 AR Premature chromosome condensation, decreased neuronal proliferation, premature differentiation SIMP Congenital MIC + - -
ASPM AR Decreased neuronal proliferation Decreased brain volume, SIMP Congenital MIC - - +/-
WDR62 AR Decreased neuronal proliferation MCDs, complex Congenital MIC, cortical dysplasia - - -
CD-K5RAP2 AR Premature differentiation Decreased brain volume, SIMP Congenital MIC - - -
CASC5 AR Decreased neuronal proliferation Decreased brain volume, SIMP Congenital MIC - - -
CENPJ AR Increased apoptosis Decreased brain volume, SIMP Congenital MIC, Seckel syndrome + - +
SASS6** AR Decreased neuronal proliferation, exact neuronal phenotype not well-understood Decreased brain volume, SIMP Congenital MIC - - +
STIL AR Neural tube defects, increased sensitivity to neurotoxic insult Holoprosencephaly, SIMP Congenital MIC - - -
CEP152 AR Abnormal centrosome structure and function, decreased neuronal proliferation Decreased brain volume, SIMP Congenital MIC, Seckel syndrome + - -
CEP63** AR Increased cell death due to increased centrosome-based mitotic errors. Decreased brain volume, SIMP Seckel syndrome + - -
NDE1 AR Decreased neuronal proliferation MCDs, complex Microhydranencephaly, lissencephaly + - -
NIN AR Defects of the anterior neuroectoderm Decreased brain volume, SIMP Seckel syndrome + - -
PCNT AR Disorganized mitotic pindles and misaggregation of chromosomes, decreased neuronal proliferation Decreased brain volume, SIMP, vascular abnormalities MOPD type II + - -
BUB1B AR Decreased neuronal proliferation, increased apoptosis Complex Mosaic variegated aneuploidy + + -
CENPE AR Potential defect of neuronal proliferation Decreased brain volume, SIMP Congenital MIC, MOPD + - -
Centro-some formation, spindle orientation, micro-tubule organization, cytokinesis KIF5C AD/ de novo Abnormal microtubule function Complex Cortical dysplasia - - +
KIF2A AD/ de novo Abnormal axonal branching with consequently reduced neuronal volume Complex Cortical dysplasia + - +
KIF11 AD/ de novo Abnormal mitotic spindles, decreased neuronal proliferation Decreased brain volume, SIMP Microcephaly-chorioretinopathy-lymphedema - - -
KIF14 AR Increased neuronal apoptosis, impaired cell migration and motility, decreased myelination Decreased brain volume, large basal cisterns, optic nerve atrophy Congenital MIC, Meckel syndrome + - -
TUBA1A AD/ de novo Abnormal neuronal migration Complex Tubulinopathy - - +
TUBG1 AD/ de novo Abnormal neuronal migration Complex Tubulinopathy - - -
TUBB2B AD/ de novo Abnormal neuronal migration Complex Tubulinopathy - - -
TBCD AR Abnormal microtubule structure and function with likely effects on neuronal proliferation and migration Complex Encephalopathy, atrophy, thin corpus callosum + - +
POC1A AR Abnormal mitotic spindles and centrioles with likely effects on neuronal proliferation and migration - Short stature, on-ychodysplasia, facial dysmorphism, hypotrichosis + - -
ZNF335 AR Reduced proliferation, defects of neuronal differentiation and migration SIMP Congenital MIC + - -
CIT AR Impaired neuronal cytokinesis, delayed mitosis, cellular blebbing, multipolar spindles, genome instability, increased apoptosis Complex Congenital MIC - - -
NCAPD2 AR Impaired chromosome segregation, reduced neuronal proliferation, reduced cell survival Decreased brain volume, SIMP Congenital MIC + - -
NCAPD3 AR Impaired chromosome segregation, reduced neuronal proliferation, reduced cell survival - - -
NCAPH** AR Impaired chromosome segregation, reduced neuronal proliferation, reduced cell survival - - -
KATNB1 AR Supernumerary centrosomes and spindle abnormalities Decreased brain volume, SIMP, cortical dysplasia Congenital MIC, cortical dysplasia - - +
Cell cycle: kinetochore CEP135 AR Fragmented or lack of centrosomes with disorganized microtubules, decreased neuronal proliferation Decreased brain volume, SIMP Congenital MIC - - -
CENPF AR Abnormal spindle orientation and ciliogenesis Decreased brain volume, SIMP Stromme syndrome - - -
CHAMP1 AD/ de novo Abnormal kinetochore-microtubule attachment Decreased brain volume, SIMP Intellectual disability, microcephaly - - -
Cell cycle: mitotic chromosome structure NCAPD2 Abnormal chromosome condensation, and sister chromatid disentanglement Decreased brain volume, SIMP AR microcephaly + - -
NCAPH AR Decreased brain volume, SIMP AR microcephaly - - -
NCAPD3 AR Decreased brain volume, SIMP AR microcephaly + -
Origin Recognition Complex ORC1 AR Abnormal DNA replication and likely abnormal neuronal proliferation SIMP MGORS + - -
ORC4 AR SIMP MGORS + - -
ORC6 AR SIMP MGORS + - -
CDT1 AR SIMP MGORS + - -
CDC6 AR SIMP MGORS + -
GMNN AR SIMP MGORS + - -
CDC45 AR SIMP MGORS + - -
DDR and chromosome stability and cell cycle regulation ATR AR/AD Exact neuronal phenotype not well-understood Complex Seckel syndrome, Familial cancer + - -
ATRIP AR Exact neuronal phenotype not well-understood SIMP Seckel syndrome + - -
RBBP8 AR Exact neuronal phenotype not well-understood Complex Seckel syndrome, Jawad syndrome + - -
NBN AR Aberrant regulation of early brain development SIMP Nijmegen breakage syndrome + + -
RAD50 AR Exact neuronal phenotype not well-understood SIMP Nijmegen breakage syndrome-like disorder + + -
MRE11A AR Exact neuronal phenotype not well-understood Complex Ataxia-telan-giectasia-like disorder - + +
PNKP AR Increased neurogenesis, defects in neuronal differentiation Complex Microcephaly with seizures and developmental delay, ataxia-oculomotor apraxia - - +
BRCA1 AR Neuroepithelial defects, reduced proliferation SIMP Fanconi anemia, complementation group S - + -
DDR and chromosome stability and cell cycle regulation BRCA2 AR Reduced neuronal proliferation SIMP Fanconi anemia, complementation group D1 - + -
LIG4 AR Exact neuronal phenotype not well-understood SIMP LIG4 syndrome + + -
NHEJ1 AR Exact neuronal phenotype not well-understood SIMP SCID with microcephaly + + -
DDX11 AR Exact neuronal phenotype not well-understood SIMP Warsaw breakage syndrome + + -
PHC1 AR Reduced proliferation, defects of differentiation SIMP Congenital MIC + - -
DNA2 AR Increased senescence, needs research SIMP Seckel syndrome + - -
XRCC2 AR Increased apoptosis of postmitotic neurons SIMP Fanconi anemia, complementation group U + + -
XRCC4 AR Increased apoptosis, reduced proliferation Complex Short stature, microcephaly, and endocrine dysfunction + + -
RECQL3 AR Exact neuronal phenotype not well-understood SIMP Bloom syndrome + + -
DONSON AR Decreased neuronal proliferation SIMP, abnormal WM, and MCDs Microcephaly-micromelia syndrome + - -
STAMBP AR Increased apoptosis Complex Microcephaly-capillary malformation + - +
CDK6 AR Exact neuronal phenotype not well-understood SIMP Congenital MIC - + -
ANKLE2 AR Decreased cell proliferation and increased apoptosis of neuroblasts SIMP, MCDs, ventricular abnormalities, ACC Congenital MIC + - +
MFSD2A AR BBB defects, neuronal cell loss, loss of transport activity SIMP Congenital MIC + - +
Cellular trafficking, fatty acid metabolism, lipid binding proteins WDFY3** AD Abnormal WNT activation, increased proliferation of apical progenitor cells, lack of neuronal differentiation, impaired cortical development (dominant-negative effect) MIC Congenital MIC - - -
COPB2** AR Increased apoptosis, reduction of upper layer neurons SIMP, thin CC, enlarged XAX, delayed myelination, progressive atrophy Congenital MIC + - +
MEGALENCEPHALY
PI3K-AKT-MTOR PIK3 CA AD/de novo (mosaic) Exact neuronal phenotype understudy, likely cell hypertrophy, abnormal neuronal organization PMG (BPP) PIK3CA-related overgrowth disorders + +/-(tentative, Wilms tumor) +
PTEN AD/ de novo Cell hypertrophy PMG, FCD PTEN-hamarto-ma tumor syndrome + + -
PIK3R2 AD/de novo Exact neuronal phenotype understudy, likely cell hypertrophy, abnormal neuronal organization PMG (BPP), mega CC Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome - - +
MTOR AD/de novo (mosaic) Cell hypertrophy, abnormal neuronal migration PMG/HMEG/FCD (depending on level of mosaicism) MTOR-related disorders - - +
CCND2 AD/de novo Increased neuronal proliferation PMG (BPP), mega CC MPPH syndrome - - +
RHEB AD/de novo Cell hypertrophy, abnormal migration - MEG-ID - - +
STRADA (LYK5) AR Abnormal neuronal lamination, mTORC1 hyperactivation VMEG, subependymal dysplasia, WM abnormalities Polyhydramnios-MEG-symptomatic epilepsy (PMSE) - - +
DEPDC5 AD/de novo Neuronal hypertrophy and abnormal neuronal organization FCD, MCDs Familial epilepsy - - +
AKT3*** AD/de novo (mosaic) Exact neuronal phenotype under study, likely cell hypertrophy, abnormal neuronal organization PMG/HMEG/FCD (depending on level of mosaicism) MPPH syndrome - - +
TSC1/TSC2 AD/de novo Neuronal hypertrophy Cortical tubers, subependymal nodules, HMEG/FCD Tuberous Sclerosis - + +
DNA methyltrans-ferases, transcription initiation, and regulators NSD1*** AD/de novo Exact neuronal phenotype not well-understood VMEG,XAX Sotos syndrome + - -
EED AD/de novo Abnormal EZH2 function, exact neuronal phenotype not well understood - Cohen-Gibson syndrome + - -
DNMT3A AD/de novo Exact neuronal phenotype not well-understood Tatton-Brown-Rahman syndrome + - +
EZH2 AD/de novo Exact neuronal phenotype not well-understood MCDs, VMEG Weaver syndrome + - +
DNA methyl-trans-ferases, transcription initiation, and regulators MYCN*** AD/de novo Decreased apoptosis - 2p24.3 duplication syndrome - + (w/ amplifications) -
MED12 X-linked Exact neuronal phenotype not well-understood Callosal abnormalities, VMEG, HET Opitz-Kaveggia syndrome Lujan (Lujan-Fryns) syndrome + - +
NFIX AD/de novo Exact neuronal phenotype not well-understood - Malan syndrome + - +
SETD2 AD/ de novo Exact neuronal phenotype not well-understood Likely complex Luscan-Lumish syndrome +/- - +
RAS-MAPK NF1 AD/ de novo RAS-MAPK mediated effects on brain development (pleitropic) VMEG, UBOs on T2 imaging, CC abnormalities Neurofibromatosis type I - + (Optic gliomas) -
SPRED1 AD/ de novo - Legius syndrome - - -
HRAS AD/ de novo CBTH, VMEG/ HYD Costello syndrome + Short stature + -
BRAF, MAP2K1, MAP2K2, KRAS AD/ de novo CBTH, VMEG/HYD, cortical atrophy, MCDs Cardiofaciocutaneous syndrome + Short stature - -
PTPN11, SOS1, RAF1, KRAS, BRAF, SHOC2, NRAS, MAP2K1 AD/ de novo CBTH, VMEG/HYD Noonan syndrome + Short stature - -
RIN2 AR - Macrocephaly-alopecia-cutis laxa-scoliosis (MACS) syndrome + Short stature - -
RAB39 XL - XLID, ASD, epilepsy - - +
RTKs FGFR3 AR Abnormal neuronal proliferation and apoptosis of cortical progenitors HYD, cervico-medullary compression, MCDs, other Achondroplasia Thanatophoric dysplasia + Multiple skeletal anomalies - -
ROR2 AR Abnormal neuronal sternness MCDs Robinow syndrome + Short stature - -
NOTCH GPC3 X-linked Abnormal cell growth and proliferation, exact neuronal phenotype not well-understood HYD, cerebellar tonsillar herniation, CC abnormalities Simpson Golabi Behmel syndrome I + + (Embryonal tumors, Wilms tumor)
NOTCH2NL*** AD/ de novo Delayed neuronal differentiation - 1q21.1 microduplication syndrome - - -
SHH PTCH1 AD/ de novo Abnormal neuronal proliferation and organization Calcifications (>90%) Nevoid basal cell carcinoma syndrome - +(PNET) -
KIF7 AR Abnormal neuronal proliferation and organization CC abnormalities (ACC) Acrocallosal syndrome + Growth retardation - +
GLI3 AD/ de novo Abnormal neuronal proliferation CC abnormalities (ACC) Greig cephalosyndactyly - - -
Cilia structure and function OFD1 X-linked Abnormal ciliary function in proliferating sells VMEG Simpson Golabi Behmel syndrome II + - -
RTTN AR Abnormal centriole formation Decreased brain volume, SIMP, cortical dysplasia, callosal, cerebellar abnormalities Microcephaly, short stature, and poly-microgyria with seizures + - +
JAK-STAT BRWD3 X-linked Abnormal cell morphology and cytoskeletal organization - XLID - - -
Abbreviations:
ACC, agenesis of the corpus callosum; AD, autosomal dominant; AR, autosomal recessive; ASD, autism spectrum disorders; BPP, bilateral frontoparietal polymicrogyria; CBTH, cerebellar tonsillar herniation; CC, corpus callosum; FCD, focal cortical dysplasia; HET, heterotopia; HMEG, hemimegalencephaly; HYD, hydrocephalus; MCDs, malformations of cortical development; MCPH, primary microcephaly genes 1-23; MEG, megalencephaly; MGORS, Meier-Gorlin syndrome 1-7; MIC, microcephaly; MOPD, microcephalic osteodysplastic primordial dwarfism; PMG, polymicrogyria; RTKs, receptor tyrosine kinases; SCID; Severe Combined Immunodeficiency; SIMP, simplified gyral pattern; UBOs, unidentified bright objects on brain MRI; VMEG, ventriculomegaly; WM, white matter; XAX, extra-axial space; XLID, X-linked intellectual disability.
Notes:
* Cancer predisposition specifically refers to germline (constitutional) cancer risk
** MIC-/MEG-associated mutations in these genes have been reported in one or few families, to date.
*** Reciprocal deletions/duplications of these gene loci are associated with MIC or MEG and include the following genes: AKT3 (1q43.q44; del MIC, dup MEG); NOTCH2NL (1q21.1; del MIC, dup MEG), MYCN (2p.24.3; del MIC, dup MEG); NSD1 (5q35.3; del MEG, dup MIC). Other MIC-MEG loci include 10q22q23 (del MEG, dup MIC) and 16p11.2 (dup MIC, dup MEG) with no MIC/MEG candidate genes identified, to our knowledge.