Entry - #617520 - MICROCEPHALY 18, PRIMARY, AUTOSOMAL DOMINANT; MCPH18 - OMIM - (OMIM.ORG)

 
ICD+
# 617520

MICROCEPHALY 18, PRIMARY, AUTOSOMAL DOMINANT; MCPH18


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
4q21.23 ?Microcephaly 18, primary, autosomal dominant 617520 AD 3 WDFY3 617485
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Head
- Microcephaly (<3 SD below mean per age)
NEUROLOGIC
Central Nervous System
- Intellectual disability, mild to moderate
- No structural brain abnormalities
MISCELLANEOUS
- One family has been reported (last curated June 2017)
MOLECULAR BASIS
- Caused by mutation in the WD repeat- and FYVE domain-containing protein 3 gene (WDFY3, 617485.0001)
▲ Close
Microcephaly, primary - PS251200 - 31 Entries
Location Phenotype Inheritance Phenotype
mapping key 		Phenotype
MIM number 		Gene/Locus Gene/Locus
MIM number
1p34.2 Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain abnormalities AR 3 616486 MFSD2A 614397
1p33 Microcephaly 7, primary, autosomal recessive AR 3 612703 STIL 181590
1p21.2 Microcephaly 14, primary, autosomal recessive AR 3 616402 SASS6 609321
1q31.3 Microcephaly 5, primary, autosomal recessive AR 3 608716 ASPM 605481
1q32.1 Microcephaly 20, primary, autosomal recessive AR 3 617914 KIF14 611279
2q11.2 ?Microcephaly 23, primary, autosomal recessive AR 3 617985 NCAPH 602332
2q13 Microcephaly 30, primary, autosomal recessive AR 3 620183 BUB1 602452
3p22.3 ?Microcephaly 29, primary, autosomal recessive AR 3 620047 PDCD6IP 608074
3q23 ?Microcephaly 19, primary, autosomal recessive AR 3 617800 COPB2 606990
4q12 Microcephaly 8, primary, autosomal recessive AR 3 614673 CEP135 611423
4q21.23 ?Microcephaly 18, primary, autosomal dominant AD 3 617520 WDFY3 617485
4q24 ?Microcephaly 13, primary, autosomal recessive AR 3 616051 CENPE 117143
5q23.2 Microcephaly 26, primary, autosomal dominant AD 3 619179 LMNB1 150340
7q21.2 ?Microcephaly 12, primary, autosomal recessive AR 3 616080 CDK6 603368
7q22.1 ?Microcephaly 25, primary, autosomal recessive AR 3 618351 TRAPPC14 618350
8p23.1 Microcephaly 1, primary, autosomal recessive AR 3 251200 MCPH1 607117
9q33.2 Microcephaly 3, primary, autosomal recessive AR 3 604804 CDK5RAP2 608201
11q25 Microcephaly 22, primary, autosomal recessive AR 3 617984 NCAPD3 609276
12p13.31 Microcephaly 21, primary, autosomal recessive AR 3 617983 NCAPD2 615638
12p13.31 ?Microcephaly 11, primary, autosomal recessive AR 3 615414 PHC1 602978
12q14.1 Microcephaly 31, primary, autosomal recessive AR 3 621507 CDK4 123829
12q23.2 ?Microcephaly 24, primary, autosomal recessive AR 3 618179 NUP37 609264
12q24.23 Microcephaly 17, primary, autosomal recessive AR 3 617090 CIT 605629
12q24.33 Microcephaly 16, primary, autosomal recessive AR 3 616681 ANKLE2 616062
13q12.12-q12.13 Microcephaly 6, primary, autosomal recessive AR 3 608393 CENPJ 609279
15q15.1 Microcephaly 4, primary, autosomal recessive AR 3 604321 KNL1 609173
15q21.1 Microcephaly 9, primary, autosomal recessive AR 3 614852 CEP152 613529
19p13.3 Microcephaly 27, primary, autosomal dominant AD 3 619180 LMNB2 150341
19q13.12 Microcephaly 2, primary, autosomal recessive, with or without cortical malformations AR 3 604317 WDR62 613583
20q13.12 Microcephaly 10, primary, autosomal recessive AR 3 615095 ZNF335 610827
22q13.2 ?Microcephaly 28, primary, autosomal recessive AR 3 619453 RRP7A 619449
▲ Close

▼ TEXT

A number sign (#) is used with this entry because of evidence that autosomal dominant primary microcephaly-18 (MCPH18) is caused by heterozygous mutation in the WDFY3 gene (617485) on chromosome 4q21. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

► Clinical Features

Kadir et al. (2016) reported a 3-generation family in which multiple individuals had microcephaly with mildly to moderately impaired intellectual development. None had apparent dysmorphic features or ocular malformations. Brain imaging showed no structural defects.


► Inheritance

The transmission pattern of MCPH18 in the family reported by Kadir et al. (2016) was consistent with autosomal dominant inheritance.


► Molecular Genetics

In affected members of a family with autosomal dominant MCPH18, Kadir et al. (2016) identified a heterozygous missense mutation in the WDFY3 gene (R2637W; 617485.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that cells transfected with the mutation had increased levels of DVL3 (601368) compared to controls. This was suggested to cause abnormal activation of WNT signaling and continued generation of apical progenitor cells without transition to differentiation and generation of the basal progenitor cell layer in the cerebral cortex, thus resulting in impaired cortical development and microcephaly. The mutation acted through a dominant-negative effect rather than haploinsufficiency. The findings indicated that autophagic attenuation of WNT signaling through removal of DVL3 aggregates by WDFY3 acts in determining human brain size.


► Animal Model

Kadir et al. (2016) found that Drosophila transfected with mutant human WDFY3 (R2637W; 617485.0001) had smaller brains. Compared to wildtype, mutant fly brains were 40 to 60% smaller in volume, denser, and very fragile and malformed, and showed clusters of disorganized cells containing WDFY3-labeled aggregates. Mutant flies also showed an abnormal rough eye phenotype with disorganized and/or fused omatids and disorganized bristles.


► REFERENCES

  1. Kadir, R., Harel, T., Markus, B., Perez, Y., Bakhrat, A., Cohen, I., Volodarsky, M., Feintsein-Linial, M., Chervinski, E., Zlotogora, J., Sivan, S., Birnbaum, R. Y., Abdu, U., Shalev, S., Birk, O. S. ALFY-controlled DVL3 autophagy regulates Wnt signaling, determining human brain size. PLoS Genet. 12: e1005919, 2016. Note: Electronic Article. [PubMed: 27008544, images, related citations] [Full Text]


Creation Date:
Cassandra L. Kniffin : 06/08/2017
Edit History:
carol : 08/01/2025
carol : 06/12/2017
carol : 06/09/2017
ckniffin : 06/08/2017

# 617520

MICROCEPHALY 18, PRIMARY, AUTOSOMAL DOMINANT; MCPH18


ORPHA: 2514;   DO: 0070295;   MONDO: 0054593;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
4q21.23 ?Microcephaly 18, primary, autosomal dominant 617520 Autosomal dominant 3 WDFY3 617485

TEXT

A number sign (#) is used with this entry because of evidence that autosomal dominant primary microcephaly-18 (MCPH18) is caused by heterozygous mutation in the WDFY3 gene (617485) on chromosome 4q21. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly, see MCPH1 (251200).

Clinical Features

Kadir et al. (2016) reported a 3-generation family in which multiple individuals had microcephaly with mildly to moderately impaired intellectual development. None had apparent dysmorphic features or ocular malformations. Brain imaging showed no structural defects.


Inheritance

The transmission pattern of MCPH18 in the family reported by Kadir et al. (2016) was consistent with autosomal dominant inheritance.


Molecular Genetics

In affected members of a family with autosomal dominant MCPH18, Kadir et al. (2016) identified a heterozygous missense mutation in the WDFY3 gene (R2637W; 617485.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that cells transfected with the mutation had increased levels of DVL3 (601368) compared to controls. This was suggested to cause abnormal activation of WNT signaling and continued generation of apical progenitor cells without transition to differentiation and generation of the basal progenitor cell layer in the cerebral cortex, thus resulting in impaired cortical development and microcephaly. The mutation acted through a dominant-negative effect rather than haploinsufficiency. The findings indicated that autophagic attenuation of WNT signaling through removal of DVL3 aggregates by WDFY3 acts in determining human brain size.


Animal Model

Kadir et al. (2016) found that Drosophila transfected with mutant human WDFY3 (R2637W; 617485.0001) had smaller brains. Compared to wildtype, mutant fly brains were 40 to 60% smaller in volume, denser, and very fragile and malformed, and showed clusters of disorganized cells containing WDFY3-labeled aggregates. Mutant flies also showed an abnormal rough eye phenotype with disorganized and/or fused omatids and disorganized bristles.


REFERENCES

  1. Kadir, R., Harel, T., Markus, B., Perez, Y., Bakhrat, A., Cohen, I., Volodarsky, M., Feintsein-Linial, M., Chervinski, E., Zlotogora, J., Sivan, S., Birnbaum, R. Y., Abdu, U., Shalev, S., Birk, O. S. ALFY-controlled DVL3 autophagy regulates Wnt signaling, determining human brain size. PLoS Genet. 12: e1005919, 2016. Note: Electronic Article. [PubMed: 27008544] [Full Text: https://doi.org/10.1371/journal.pgen.1005919]


Creation Date:
Cassandra L. Kniffin : 06/08/2017

Edit History:
carol : 08/01/2025
carol : 06/12/2017
carol : 06/09/2017
ckniffin : 06/08/2017



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OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2026 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2026 Johns Hopkins University.
Printed: May 21, 2026