Entry - #616080 - MICROCEPHALY 12, PRIMARY, AUTOSOMAL RECESSIVE; MCPH12 - OMIM - (MIRROR)

 
ICD+
# 616080

MICROCEPHALY 12, PRIMARY, AUTOSOMAL RECESSIVE; MCPH12


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
7q21.2 ?Microcephaly 12, primary, autosomal recessive 616080 AR 3 CDK6 603368
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Head
- Microcephaly, primary (-4 to -6 SD)
Face
- Sloping forehead
NEUROLOGIC
Central Nervous System
- Intellectual disability, mild
- Simplified gyral pattern
MISCELLANEOUS
- One consanguineous Pakistani family has been reported (last curated November 2014)
MOLECULAR BASIS
- Caused by mutation in the cyclin-dependent kinase 6 gene (CDK6, 603368.0001)
▲ Close
Microcephaly, primary - PS251200 - 30 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 MAP11 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
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 recessive primary microcephaly-12 (MCPH12) is caused by homozygous mutation in the CDK6 gene (603368) on chromosome 7q21. One such family has been reported.

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

▼ Clinical Features

Hussain et al. (2013) reported a highly consanguineous 8-generation Pakistani family in which 10 individuals had primary microcephaly (-4 to -6 SD). All 10 patients had a sloping forehead and mild intellectual disability, but had understandable speech and appropriate social behavior; all could dress independently. None had seizures or other neurologic abnormalities. Brain imaging of 2 patients showed a simplified gyral pattern with no gross structural abnormalities.


▼ Inheritance

The transmission pattern of MCPH12 in the family reported by Hussain et al. (2013) was consistent with autosomal recessive inheritance.


▼ Mapping

By genomewide linkage analysis of a large consanguineous Pakistani family with autosomal recessive primary microcephaly, Hussain et al. (2013) found linkage to an 8-cM region on chromosome 7q21.11-q21.3 (maximum multipoint lod score of 10.47).


▼ Molecular Genetics

In affected members of a Pakistani family with MCPH12, Hussain et al. (2013) identified a homozygous missense mutation in the CDK6 gene (A197T; 603368.0001). The mutation, which was found by homozygosity mapping, candidate gene analysis, and whole-exome sequencing, segregated with the disorder in the family. During interphase, patient cells showed normal CDK6 localization, but during mitosis, mutant CDK6 did not localize at the centrosome, the mitotic spindles were disorganized with abnormal microtubule formation, and the nuclei were misshapen. Supernumerary centrosomes were also observed during mitosis. Patient cells showed a reduced growth rate and increased apoptosis compared to controls, as well as impaired motility and polarity. Hussain et al. (2013) postulated a loss-of-function effect of the mutation because the abnormalities observed in patient cells were similar to those observed in in vitro CDK6 knockdown studies. The findings suggested that the mutation affects cell proliferation during neurogenesis.


▼ REFERENCES

  1. Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. Hum. Molec. Genet. 22: 5199-5214, 2013. [PubMed: 23918663, related citations] [Full Text]


Creation Date:
Cassandra L. Kniffin : 11/4/2014
Edit History:
carol : 05/12/2017
carol : 11/05/2014
ckniffin : 11/5/2014

# 616080

MICROCEPHALY 12, PRIMARY, AUTOSOMAL RECESSIVE; MCPH12


ORPHA: 2512;   DO: 0070284;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
7q21.2 ?Microcephaly 12, primary, autosomal recessive 616080 Autosomal recessive 3 CDK6 603368

TEXT

A number sign (#) is used with this entry because of evidence that autosomal recessive primary microcephaly-12 (MCPH12) is caused by homozygous mutation in the CDK6 gene (603368) on chromosome 7q21. One such family has been reported.

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

Clinical Features

Hussain et al. (2013) reported a highly consanguineous 8-generation Pakistani family in which 10 individuals had primary microcephaly (-4 to -6 SD). All 10 patients had a sloping forehead and mild intellectual disability, but had understandable speech and appropriate social behavior; all could dress independently. None had seizures or other neurologic abnormalities. Brain imaging of 2 patients showed a simplified gyral pattern with no gross structural abnormalities.


Inheritance

The transmission pattern of MCPH12 in the family reported by Hussain et al. (2013) was consistent with autosomal recessive inheritance.


Mapping

By genomewide linkage analysis of a large consanguineous Pakistani family with autosomal recessive primary microcephaly, Hussain et al. (2013) found linkage to an 8-cM region on chromosome 7q21.11-q21.3 (maximum multipoint lod score of 10.47).


Molecular Genetics

In affected members of a Pakistani family with MCPH12, Hussain et al. (2013) identified a homozygous missense mutation in the CDK6 gene (A197T; 603368.0001). The mutation, which was found by homozygosity mapping, candidate gene analysis, and whole-exome sequencing, segregated with the disorder in the family. During interphase, patient cells showed normal CDK6 localization, but during mitosis, mutant CDK6 did not localize at the centrosome, the mitotic spindles were disorganized with abnormal microtubule formation, and the nuclei were misshapen. Supernumerary centrosomes were also observed during mitosis. Patient cells showed a reduced growth rate and increased apoptosis compared to controls, as well as impaired motility and polarity. Hussain et al. (2013) postulated a loss-of-function effect of the mutation because the abnormalities observed in patient cells were similar to those observed in in vitro CDK6 knockdown studies. The findings suggested that the mutation affects cell proliferation during neurogenesis.


REFERENCES

  1. Hussain, M. S., Baig, S. M., Neumann, S., Peche, V. S., Szczepanski, S., Nurnberg, G., Tariq, M., Jameel, M., Khan, T. N., Fatima, A., Malik, N. A., Ahmad, I., and 9 others. CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly. Hum. Molec. Genet. 22: 5199-5214, 2013. [PubMed: 23918663] [Full Text: https://doi.org/10.1093/hmg/ddt374]


Creation Date:
Cassandra L. Kniffin : 11/4/2014

Edit History:
carol : 05/12/2017
carol : 11/05/2014
ckniffin : 11/5/2014



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® 1966-2024 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® 1966-2024 Johns Hopkins University.
Printed: Nov. 29, 2024