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Microcephaly 12, primary, autosomal recessive(MCPH12)

MedGen UID:
863593
•Concept ID:
C4015156
•
Disease or Syndrome
Synonyms: MCPH12; MICROCEPHALY 12, PRIMARY, AUTOSOMAL RECESSIVE
 
Gene (location): CDK6 (7q21.2)
 
Monarch Initiative: MONDO:0014484
OMIM®: 616080

Definition

Any autosomal recessive primary microcephaly in which the cause of the disease is a mutation in the CDK6 gene. [from MONDO]

Clinical features

From HPO
Intellectual disability, mild
MedGen UID:
10044
•Concept ID:
C0026106
•
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
See: Feature record | Search on this feature
Simplified gyral pattern
MedGen UID:
413664
•Concept ID:
C2749675
•
Finding
An abnormality of the cerebral cortex with fewer gyri but with normal cortical thickness. This pattern is usually often associated with congenital microcephaly.
See: Feature record | Search on this feature
Intellectual disability
MedGen UID:
811461
•Concept ID:
C3714756
•
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
See: Feature record | Search on this feature
Microcephaly
MedGen UID:
1644158
•Concept ID:
C4551563
•
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
See: Feature record | Search on this feature
Sloping forehead
MedGen UID:
346640
•Concept ID:
C1857679
•
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
See: Feature record | Search on this feature
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Recent clinical studies

Etiology

Proteome changes in autosomal recessive primary microcephaly.
Zaqout S, Mannaa A, Klein O, Krajewski A, Klose J, Luise-Becker L, Elsabagh A, Ferih K, Kraemer N, Ravindran E, Makridis K, Kaindl AM
Ann Hum Genet 2023 Mar;87(1-2):50-62. Epub 2022 Nov 29 doi: 10.1111/ahg.12489. PMID: 36448252
TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly.
Cavallin M, Maillard C, Hully M, Philbert M, Boddaert N, Reilly ML, Nitschké P, Bery A, Bahi-Buisson N
Eur J Med Genet 2018 Dec;61(12):729-732. Epub 2018 May 25 doi: 10.1016/j.ejmg.2018.05.002. PMID: 29758293
Genetics and biology of microcephaly and lissencephaly.
Mochida GH
Semin Pediatr Neurol 2009 Sep;16(3):120-6. doi: 10.1016/j.spen.2009.07.001. PMID: 19778709Free PMC Article
Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation.
Jongmans W, Vuillaume M, Chrzanowska K, Smeets D, Sperling K, Hall J
Mol Cell Biol 1997 Sep;17(9):5016-22. doi: 10.1128/MCB.17.9.5016. PMID: 9271379Free PMC Article

Diagnosis

Further insights into the spectrum phenotype of TRAPPC9 and CDK5RAP2 genes, segregating independently in a large Tunisian family with intellectual disability and microcephaly.
Ben Ayed I, Bouchaala W, Bouzid A, Feki W, Souissi A, Ben Nsir S, Ben Said M, Sammouda T, Majdoub F, Kharrat I, Kamoun F, Elloumi I, Kamoun H, Tlili A, Masmoudi S, Triki C
Eur J Med Genet 2021 Dec;64(12):104373. Epub 2021 Oct 29 doi: 10.1016/j.ejmg.2021.104373. PMID: 34737153
Novel neuroclinical findings of autosomal recessive primary microcephaly 15 in a consanguineous Iranian family.
Razmara E, Azimi H, Tavasoli AR, Fallahi E, Sheida SV, Eidi M, Bitaraf A, Farjami Z, Daneshmand MA, Garshasbi M
Eur J Med Genet 2020 Dec;63(12):104096. Epub 2020 Nov 11 doi: 10.1016/j.ejmg.2020.104096. PMID: 33186761
Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy.
Tsutsumi M, Yokoi S, Miya F, Miyata M, Kato M, Okamoto N, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Saitoh S, Kurahashi H
Eur J Hum Genet 2016 Dec;24(12):1702-1706. Epub 2016 Sep 21 doi: 10.1038/ejhg.2016.119. PMID: 27650967Free PMC Article
Genetics and biology of microcephaly and lissencephaly.
Mochida GH
Semin Pediatr Neurol 2009 Sep;16(3):120-6. doi: 10.1016/j.spen.2009.07.001. PMID: 19778709Free PMC Article
What primary microcephaly can tell us about brain growth.
Cox J, Jackson AP, Bond J, Woods CG
Trends Mol Med 2006 Aug;12(8):358-66. Epub 2006 Jul 10 doi: 10.1016/j.molmed.2006.06.006. PMID: 16829198

Prognosis

Disease relevance of rare VPS13B missense variants for neurodevelopmental Cohen syndrome.
Zorn M, Kühnisch J, Bachmann S, Seifert W
Sci Rep 2022 Jun 11;12(1):9686. doi: 10.1038/s41598-022-13717-w. PMID: 35690661Free PMC Article
Primary and Secondary Microcephaly, Global Developmental Delay, and Seizure in Two Siblings Caused by a Novel Missense Variant in the ZNF335 Gene.
Tavasoli AR, Memar EHE, Ashrafi MR, Hosseini SMM, Haghighi R, Ghabeli H, Pourbakhtyaran E, Rasoulinezhad M, Mohammadi P, Heidari M
J Mol Neurosci 2022 Apr;72(4):719-729. Epub 2022 Jan 4 doi: 10.1007/s12031-021-01955-y. PMID: 34982360
A Homozygous AKNA Frameshift Variant Is Associated with Microcephaly in a Pakistani Family.
Waseem SS, Moawia A, Budde B, Tariq M, Khan A, Ali Z, Khan S, Iqbal M, Malik NA, Haque SU, Altmüller J, Thiele H, Hussain MS, Cirak S, Baig SM, Nürnberg P
Genes (Basel) 2021 Sep 24;12(10) doi: 10.3390/genes12101494. PMID: 34680889Free PMC Article
ASPM predicts poor prognosis and regulates cell proliferation in bladder cancer.
Gao ZY, Yu F, Jia HX, Ye Z, Yao SJ
Kaohsiung J Med Sci 2020 Dec;36(12):1021-1029. Epub 2020 Aug 6 doi: 10.1002/kjm2.12284. PMID: 32767492
PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.
Zaki MS, Bhat G, Sultan T, Issa M, Jung HJ, Dikoglu E, Selim L, G Mahmoud I, Abdel-Hamid MS, Abdel-Salam G, Marin-Valencia I, Gleeson JG
Ann Neurol 2016 Jul;80(1):59-70. Epub 2016 Jun 1 doi: 10.1002/ana.24678. PMID: 27130255Free PMC Article

Clinical prediction guides

Proteome changes in autosomal recessive primary microcephaly.
Zaqout S, Mannaa A, Klein O, Krajewski A, Klose J, Luise-Becker L, Elsabagh A, Ferih K, Kraemer N, Ravindran E, Makridis K, Kaindl AM
Ann Hum Genet 2023 Mar;87(1-2):50-62. Epub 2022 Nov 29 doi: 10.1111/ahg.12489. PMID: 36448252
Primary and Secondary Microcephaly, Global Developmental Delay, and Seizure in Two Siblings Caused by a Novel Missense Variant in the ZNF335 Gene.
Tavasoli AR, Memar EHE, Ashrafi MR, Hosseini SMM, Haghighi R, Ghabeli H, Pourbakhtyaran E, Rasoulinezhad M, Mohammadi P, Heidari M
J Mol Neurosci 2022 Apr;72(4):719-729. Epub 2022 Jan 4 doi: 10.1007/s12031-021-01955-y. PMID: 34982360
Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy.
Tsutsumi M, Yokoi S, Miya F, Miyata M, Kato M, Okamoto N, Tsunoda T, Yamasaki M, Kanemura Y, Kosaki K, Saitoh S, Kurahashi H
Eur J Hum Genet 2016 Dec;24(12):1702-1706. Epub 2016 Sep 21 doi: 10.1038/ejhg.2016.119. PMID: 27650967Free PMC Article
A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.
Darvish H, Esmaeeli-Nieh S, Monajemi GB, Mohseni M, Ghasemi-Firouzabadi S, Abedini SS, Bahman I, Jamali P, Azimi S, Mojahedi F, Dehghan A, Shafeghati Y, Jankhah A, Falah M, Soltani Banavandi MJ, Ghani M, Garshasbi M, Rakhshani F, Naghavi A, Tzschach A, Neitzel H, Ropers HH, Kuss AW, Behjati F, Kahrizi K, Najmabadi H
J Med Genet 2010 Dec;47(12):823-8. Epub 2010 Oct 26 doi: 10.1136/jmg.2009.076398. PMID: 20978018
Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.
Passemard S, Titomanlio L, Elmaleh M, Afenjar A, Alessandri JL, Andria G, de Villemeur TB, Boespflug-Tanguy O, Burglen L, Del Giudice E, Guimiot F, Hyon C, Isidor B, Mégarbané A, Moog U, Odent S, Hernandez K, Pouvreau N, Scala I, Schaer M, Gressens P, Gerard B, Verloes A
Neurology 2009 Sep 22;73(12):962-9. doi: 10.1212/WNL.0b013e3181b8799a. PMID: 19770472

Supplemental Content

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    Related information

    • ClinVar
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      Related information in NCBI Gene
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    • GTR(Clinical)
      Clinical tests in GTR
    • OMIM
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    • OMIM(Genes)
      OMIM records containing genes associated with phenotypes registered in MedGen
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      Related information in PubMed Central Links
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