Table 2.

Monogenic Disorders with Congenital Microcephaly and Intellectual Disability to Consider in the Differential Diagnosis of ASPM Primary Microcephaly

Disorder/Phenotype 1Gene(s)MOIClinical Features Distinguishing the Disorder from ASPM-MCPH
MCPH (OMIM PS251200)ANKLE2
CDK5RAP2
CDK6
CENPE
CPAP (CENPJ)
CEP135
CEP152
CIT
COPB2
KIF14
KNL1
MAP11
MCPH1
MFSD2A
NCAPD2
NCAPD3
NCAPH
NUP37
PHC1
SASS6
STIL
WDFY3
WDR62
ZNF335		AR

(AD) 2

  • ANKLE2-, CPAP-, CEP152-, KIF14-, NCAPD2-, PHC-, & ZNF335-MCPH: may have IUGR w/subsequent short stature
  • MFSD2A-MCPH: may have hydrocephalus
  • STIL-MCPH: may have holoprosencephaly
  • WDR62-MCPH: often severe cortical dysplasia (DD w/the cortical malformation, complex phenotypic series)
  • ZNF335-MCPH: early lethality
Microcephaly-micromelia syndrome (OMIM 251230) DONSON AR
  • Short stature
  • Inconstant anomalies of forearm
Meier-Gorlin syndrome (OMIM PS224690) CDC45
CDC6
CDT1
GMNN
MCM5
ORC1
ORC4
ORC6 		AR
(AD) 3
  • ORC1 Meier-Gorlin syndrome: short stature
  • Mammary hypoplasia in females
  • Bilateral microtia & aplasia or hypoplasia of the patellae are characteristic but inconstant.
  • ID uncommon
Cortical dysplasia, complex, w/other brain malformations (OMIM PS614039, Congenital Fibrosis of the Extraocular Muscles, Tubulinopathies Overview) CTNNA2
KIF2A
KIF5C
TUBA8
TUBB
TUBB2A
TUBB2B
TUBB3
TUBG1 		AD
(AR) 4
  • Brain dysplasia of variable severity
  • Fusion between caudate & putamen nuclei w/indistinct anterior arm of the internal capsule
  • Neonatal seizures
Seckel syndrome (OMIM PS210600)ATR
CPAP (CENPJ)
CEP152
CEP63
DNA2
NIN
NSMCE2
RBBP8

TRAIP

AR
  • IUGR
  • Severe short stature (>3 SD below the mean)
  • Microcephaly may be disproportionate (in SD) compared to height.
  • Beaked nose
  • Sloping forehead
Microcephalic osteodysplastic dwarfism (MOPD) type II PCNT AR
  • IUGR w/subsequent very short stature
  • Mild skeletal dysplasia
  • Risk of brain hemorrhages
RNU4ATAC disorders RNU4ATAC AR
  • IUGR w/subsequent short stature
  • Brain malformations
  • Ocular & auditory sensory deficit
  • Encompass a spectrum of 3 phenotypes: primary MOPD type I, Roifman syndrome, & Lowry Wood syndrome
Microcephaly & chorioretinopathy (MCCRP) (OMIM PS251270) PLK4
TUBGCP4
TUBGCP6 		AR
  • Chorioretinopathy (inconstant)
  • PLK4-MCCRP: IUGR w/subsequent short stature
Microcephaly w/or w/o chorioretinopathy, lymphedema, or ID (OMIM 152950) KIF11 AD
  • Chorioretinopathy & lymphedema (inconstant)
  • ID uncommon
Asparagine synthetase deficiency ASNS AR
  • Low CSF asparagine level
  • Progressive encephalopathy w/cortical atrophy & seizures
Serine biosynthesis defects PHGDH
PSPH
PSAT1 		AR
  • Low CSF serine level
  • Neonatal seizures
DYRK1A ID syndrome DYRK1A AD
  • Distinctive facies: bitemporal narrowing, deep-set eyes, large simple ears, pointed nasal tip

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MCPH = primary hereditary microcephaly; MOI = mode of inheritance; SD = standard deviation(s)

1.

Disorders are associated with intellectual disability unless otherwise noted.

2.

MCPH is inherited in an autosomal recessive manner with the exception of WDFY3-MCPH, which is inherited in an autosomal dominant manner.

3.

Meier-Gorlin syndrome is inherited in an autosomal recessive manner with the exception of GMNN Meier-Gorlin syndrome, which is inherited in an autosomal dominant manner.

4.

Cortical dysplasia, complex, with other brain malformations (CDCBM) is inherited in an autosomal dominant manner with the exception of CTNNA2- and TUBA8-CDCBM, which are inherited in an autosomal recessive manner.

From: ASPM Primary Microcephaly

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.