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Autosomal recessive primary microcephaly

MedGen UID:: 777995
•Concept ID:: C3711387
•: Disease or Syndrome

Synonym:	MCPH syndrome
SNOMED CT:	Autosomal recessive primary microcephaly (715981004); Microcephalia vera (715981004); True microcephaly (715981004)
Modes of inheritance:	Autosomal recessive inheritance MedGen UID: 141025 •Concept ID: C0441748 • Intellectual Product Source: Orphanet A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). Autosomal recessive inheritance (Orphanet)

Related genes: Gene(s) associated with related conditions. For conditions in a hierarchy, the parent condition will list the genes associated with the children conditions.	WDR62, ASPM, SASS6, MFSD2A, MCPH1, ZNF335, KNL1, CENPJ, CDK5RAP2, CEP152, CEP135, STIL, PHC1, CENPE, CDK6

Monarch Initiative:	MONDO:0016660
OMIM® Phenotypic series:	PS251200
Orphanet:	ORPHA2512

Definition

Autosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development with features of reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment. It is more common in specific populations, e.g. northern Pakistanis. Consanguinity appears to play a role in incidence. Patients have a reduction in head circumference at birth of at least 2 standard deviations below ethnically matched, age- and sex-related mean values. Caused by mutations in MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, STIL, CEP63, CEP135 , CASC5 and PHC1. These mutations appear to lead to reduced generation of cerebral cortical neurons during embryonic neurogenesis. Inheritance is autosomal recessive. [from SNOMEDCT_US]

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

Developmental disorder
- Neurodevelopmental disorder
  - Developmental disorder
    - Neurodevelopmental disorder
      - Brain Development Abnormality
        Isolated congenital microcephaly
        Autosomal recessive primary microcephaly
        Microcephalic primordial dwarfism due to ZNF335 deficiency
        Microcephaly 1, primary, autosomal recessive
        Microcephaly 11, primary, autosomal recessive
        Microcephaly 12, primary, autosomal recessive
        Microcephaly 13, primary, autosomal recessive
        Microcephaly 14, primary, autosomal recessive
        Microcephaly 15, primary, autosomal recessive
        Microcephaly 2, primary, autosomal recessive, with or without cortical malformations
        Microcephaly 3, primary, autosomal recessive
        Microcephaly 4, primary, autosomal recessive
        Microcephaly 5, primary, autosomal recessive
        Microcephaly 6, primary, autosomal recessive
        Microcephaly 7, primary, autosomal recessive
        Microcephaly 8, primary, autosomal recessive
        Microcephaly 9, primary, autosomal recessive

Professional guidelines

PubMed

Novel SASS6 compound heterozygous mutations in a Chinese family with primary autosomal recessive microcephaly.

Zhang Y, Li H, Pang J, Peng Y, Shu L, Wang H
Clin Chim Acta 2019 Apr;491:15-18. Epub 2019 Jan 10 doi: 10.1016/j.cca.2019.01.007. PMID: 30639237

Prenatal diagnosis of primary microcephaly in two consanguineous families by confrontation of morphometry with DNA data.

Tunca Y, Vurucu S, Parma J, Akin R, Désir J, Baser I, Ergun A, Abramowicz M
Prenat Diagn 2006 May;26(5):449-53. doi: 10.1002/pd.1434. PMID: 16532515

See all (2)

Recent clinical studies

Etiology

Genetic susceptibility of vitamin D receptor gene polymorphisms on autosomal recessive primary microcephaly patients in Pakistani population: a case-control and in-silico study.

Aslam K, Anjum I, Aslam K, Haq R, Bashir R
Mol Biol Rep 2023 Oct;50(10):8049-8059. Epub 2023 Aug 4 doi: 10.1007/s11033-023-08681-1. PMID: 37541996

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

Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.

Ravindran E, Jühlen R, Vieira-Vieira CH, Ha T, Salzberg Y, Fichtman B, Luise-Becker L, Martins N, Picker-Minh S, Bessa P, Arts P, Jackson MR, Taranath A, Kamien B, Barnett C, Li N, Tarabykin V, Stoltenburg-Didinger G, Harel A, Selbach M, Dickmanns A, Fahrenkrog B, Hu H, Scott H, Kaindl AM
Hum Mol Genet 2021 Nov 1;30(22):2068-2081. doi: 10.1093/hmg/ddab160. PMID: 34170319 Free PMC Article

A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature.

Zombor M, Kalmár T, Nagy N, Berényi M, Telcs B, Maróti Z, Brandau O, Sztriha L
J Appl Genet 2019 May;60(2):151-162. Epub 2019 Feb 1 doi: 10.1007/s13353-019-00486-y. PMID: 30706430

Autosomal recessive primary microcephaly due to ASPM mutations: An update.

Létard P, Drunat S, Vial Y, Duerinckx S, Ernault A, Amram D, Arpin S, Bertoli M, Busa T, Ceulemans B, Desir J, Doco-Fenzy M, Elalaoui SC, Devriendt K, Faivre L, Francannet C, Geneviève D, Gérard M, Gitiaux C, Julia S, Lebon S, Lubala T, Mathieu-Dramard M, Maurey H, Metreau J, Nasserereddine S, Nizon M, Pierquin G, Pouvreau N, Rivier-Ringenbach C, Rossi M, Schaefer E, Sefiani A, Sigaudy S, Sznajer Y, Tunca Y, Guilmin Crepon S, Alberti C, Elmaleh-Bergès M, Benzacken B, Wollnick B, Woods CG, Rauch A, Abramowicz M, El Ghouzzi V, Gressens P, Verloes A, Passemard S
Hum Mutat 2018 Mar;39(3):319-332. Epub 2018 Jan 16 doi: 10.1002/humu.23381. PMID: 29243349

See all (11)

Diagnosis

Misclassification in defining and diagnosing microcephaly.

Kalmin MM, Gower EW, Stringer EM, Bowman NM, Rogawski McQuade ET, Westreich D
Paediatr Perinat Epidemiol 2019 Jul;33(4):286-290. doi: 10.1111/ppe.12561. PMID: 31347726 Free PMC Article

Autosomal Recessive Primary Microcephaly (MCPH): An Update.

Zaqout S, Morris-Rosendahl D, Kaindl AM
Neuropediatrics 2017 Jun;48(3):135-142. Epub 2017 Apr 11 doi: 10.1055/s-0037-1601448. PMID: 28399591

Molecular genetics of human primary microcephaly: an overview.

Faheem M, Naseer MI, Rasool M, Chaudhary AG, Kumosani TA, Ilyas AM, Pushparaj P, Ahmed F, Algahtani HA, Al-Qahtani MH, Saleh Jamal H
BMC Med Genomics 2015;8 Suppl 1(Suppl 1):S4. Epub 2015 Jan 15 doi: 10.1186/1755-8794-8-S1-S4. PMID: 25951892 Free PMC Article

Autosomal Recessive Primary Microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum.

Mahmood S, Ahmad W, Hassan MJ
Orphanet J Rare Dis 2011 Jun 13;6:39. doi: 10.1186/1750-1172-6-39. PMID: 21668957 Free 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

See all (31)

Therapy

A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature.

Zombor M, Kalmár T, Nagy N, Berényi M, Telcs B, Maróti Z, Brandau O, Sztriha L
J Appl Genet 2019 May;60(2):151-162. Epub 2019 Feb 1 doi: 10.1007/s13353-019-00486-y. PMID: 30706430

Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins CPAP and STIL.

Kitagawa D, Kohlmaier G, Keller D, Strnad P, Balestra FR, Flückiger I, Gönczy P
J Cell Sci 2011 Nov 15;124(Pt 22):3884-93. Epub 2011 Nov 18 doi: 10.1242/jcs.089888. PMID: 22100914

See all (2)

Prognosis

Recurrence mutation in RBBP8 gene causing non-syndromic autosomal recessive primary microcephaly; geometric simulation approach for insight into predicted computational models.

Batool T, Irshad S, Riaz M, Mahmood Baig S, Nuernberg P, Hussain MS
J Hum Genet 2023 Jul;68(7):469-475. Epub 2023 Mar 3 doi: 10.1038/s10038-023-01132-6. PMID: 36864288

Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.

Misclassification in defining and diagnosing microcephaly.

Kalmin MM, Gower EW, Stringer EM, Bowman NM, Rogawski McQuade ET, Westreich D
Paediatr Perinat Epidemiol 2019 Jul;33(4):286-290. doi: 10.1111/ppe.12561. PMID: 31347726 Free PMC Article

A novel splice-site mutation in the ASPM gene underlies autosomal recessive primary microcephaly.

Hashmi JA, Al-Harbi KM, Ramzan K, Albalawi AM, Mehmood A, Samman MI, Basit S
Ann Saudi Med 2016 Nov-Dec;36(6):391-396. doi: 10.5144/0256-4947.2016.391. PMID: 27920410 Free PMC Article

Molecular genetics of human primary microcephaly: an overview.

See all (19)

Clinical prediction guides

Proteome changes in autosomal recessive primary microcephaly.

Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.

Misclassification in defining and diagnosing microcephaly.

Kalmin MM, Gower EW, Stringer EM, Bowman NM, Rogawski McQuade ET, Westreich D
Paediatr Perinat Epidemiol 2019 Jul;33(4):286-290. doi: 10.1111/ppe.12561. PMID: 31347726 Free PMC Article

Expanding the clinical spectrum of biallelic ZNF335 variants.

Stouffs K, Stergachis AB, Vanderhasselt T, Dica A, Janssens S, Vandervore L, Gheldof A, Bodamer O, Keymolen K, Seneca S, Liebaers I, Jayaraman D, Hill HE, Partlow JN, Walsh CA, Jansen AC
Clin Genet 2018 Aug;94(2):246-251. Epub 2018 May 3 doi: 10.1111/cge.13260. PMID: 29652087 Free PMC Article

Molecular genetics of human primary microcephaly: an overview.

See all (37)

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Autosomal recessive primary microcephaly

Definition

Term Hierarchy

Professional guidelines

PubMed

Recent clinical studies

Etiology

Diagnosis

Therapy

Prognosis

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