Table 2.

PMG-Associated Genes Grouped by Pathway/Pathology

Pathway/
Pathology
Gene 1Head Size 2Brain FindingsDisorder NameMOIReference 3
MACMICN/MS
mTORopathies AKT3 xBilateral perisylvian PMGMPPH syndromeAD MPPH Syndrome
CCND2 x
MTOR xSmith-Kingsmore syndromeADOMIM 616638
PI4KA xPerisylvian PMGAR PI4KA-Related Disorder
PIK3CA xBilateral perisylvian PMGMCAP syndromeSee footnote 5. PIK3CA-Related Segmental Overgrowth
PIK3R2 xMPPH syndromeAD MPPH Syndrome
PTEN xDiffuse, focal, or multifocal PMGADElia et al [2012], Saletti et al [2017]
Tubulinopathies DYNC1H1 xxFrontal or diffuse PMGADOMIM 600112
KIF5C xPerisylvian PMGADOMIM 615282
TUBA1A xxDiffuse, focal, or multifocal PMG; bilateral, asymmetric, perisylvian PMGLissencephaly 3AD Tubulinopathies Overview
TUBB xPMGAD
TUBB2A xBilateral, asymmetric, anterior predominant PMGAD
TUBB2B xx
TUBB3 xxFrontoparietal PMGAD
Cobblestone
dysplasia – alpha
dystroglycan-
opathies
FKTN xDiffuse (cerebral & cerebellar) PMGAR Fukuyama Congenital Muscular Dystrophy
POMGNT1 xPMGAROMIM 606822
POMT2 xPMGAROMIM 607439
Cobblestone
dysplasia –
other (incl
laminopathies
& congenital
disorders of
glycosylation)
ADGRG1 (GPR56)xBilateral frontoparietal PMGAROMIM 604110
COL3A1 xxDiffuse cobblestone cortex; PMG A > PAR Horn et al [2017]
ATP6V0A2 xxFrontoparietal PMGAutosomal recessive cutis laxa type 2AAR ATP6V0A2-Related Cutis Laxa
LAMA2 xOccipital PMG; white-matter signal abnormalitiesMuscular dystrophy, congenital merosin-deficient, 1AAROMIM 607855
LAMB1 xxPorencephaly; cobblestone lissencephaly P > ALissencephaly 5AROMIM 615191
LAMC3 xOccipital PMGAROMIM 614115
SNAP29 xPerisylvian or diffuse PMGAROMIM 609528
SRD5A3 xFrontal PMGSRD5A3-CDG (CDG-Iq)AR Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview
Other BICD2 xPerisylvian PMGAD Ravenscroft et al [2016]
COL18A1 xFrontal PMGKnobloch syndrome 1AR Keren et al [2007]
DDX3X xxFrontoparietal or diffuse PMGDDX3X-related neurodevelopmental disorderXL DDX3X-Related Neurodevelopmental Disorder
EML1 xRibbon-like heterotopia w/overlying PMG; ACCAROMIM 600348
EOMES (TBR2)xBilateral perisylvian or diffuse PMGAROMIM 604615
EZH2 xBilateral perisylvian PMGWeaver syndromeAD EZH2-Related Overgrowth
FIG4 xxBilateral or temporo-occipital PMGAROMIM 612691
GPSM2 xParasagittal PMG; ACCChudley-McCollough syndromeAROMIM 604213
GRIN1 xExtensive bilateral PMGAD GRIN1-Related Neurodevelopmental Disorder
GRIN2B xxDiffuse PMGAD GRIN2B-Related Neurodevelopmental Disorder
KIFBP (KIAA1279)xDiffuse PMGGoldberg-Shprintzen syndromeAROMIM 609460
MAP1B Perisylvian PMG; PNHAD Heinzen et al [2018]
NDE1 xDiffuse PMGAROMIM 609449
NEDD4L xBilateral perisylvian PMG; PNHAD Kato et al [2017]
OCLN xBand-like calcifications w/diffuse PMGPseudo-TORCH syndrome 1AROMIM 251290
OFD1 xFrontal and parietal PMGJoubert syndrome (XLR); orofaciodigital syndrome 1 (XLD)XL Joubert Syndrome
PAX6 xVariable temporal PMGAROMIM 607108
RAB18 xxDiffuse or frontal PMGRAB18 deficiency 4AR RAB18 Deficiency
RAB3GAP1 xx
RAB3GAP2 xx
RTTN xVariable diffuse, asymmetric PMGAROMIM 614833
TBC1D20 xDiffuse or bilateral frontal PMGRAB18 deficiency 4AR RAB18 Deficiency
TCTN1 xFrontal PMGJoubert syndromeAR Joubert Syndrome
TMEM216 xVariable PMGMeckel-Gruber syndrome, Joubert syndromeAR
WDR62 x± diffuse or asymmetric PMGAR WDR62 Primary Microcephaly

Note: The table does not list genes that can be associated with PMG and metabolic disorders (Table 3), disorders of peroxisomal biogenesis (see Zellweger Spectrum Disorder), or mitochondrial disorders (see Mitochondrial Disorders Overview).

A = anterior; ACC = absence of the corpus callosum; AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; MCAP = megalencephaly-capillary malformation-PMG; MOI = mode of inheritance; MPPH = megalencephaly-polymicrogyria-polydactyly-hydrocephalus; P = posterior; PNH = periventricular nodular heterotopia; XL = X-linked; XLD = X-linked dominant; XLR = X-linked recessive

1.

Genes are in alphabetic order.

2.

Head size:

N/MS = normal / mildly small (i.e., head circumference >3 SD and <97%)

MIC = severe microcephaly (i.e., birth head circumference <3 SD or earliest HC <4 SD)

MAC = macrocephaly (i.e., head circumference >97%)

3.

GeneReview, citation, or OMIM entry

4.

RAB18 deficiency is a spectrum that includes Warburg micro syndrome (at the severe end) and Martsolf syndrome (at the mild end). Additional findings are eye involvement (bilateral congenital cataracts, microphthalmia, and microcornea); severe-to-profound intellectual disability; and hypogonadism.

5.

Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for pathogenic variants in PIK3CA, suggesting that mutation occurred post fertilization in one cell of the multicellular embryo. Two of 24 affected individuals had a de novo germline pathogenic variant in PIK3CA.

From: Polymicrogyria Overview

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