TY - JOUR T1 - Homozygous mutation in <em>MCM7</em> causes autosomal recessive primary microcephaly and intellectual disability JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmedgenet-2020-107518 SP - jmedgenet-2020-107518 AU - Ethiraj Ravindran AU - Cynthia Gutierrez de Velazco AU - Ali Ghazanfar AU - Nadine Kraemer AU - Abdul Waheed AU - Mohsan Hanif AU - Sadia Mughal AU - Alessandro Prigione AU - Na Li AU - Xiang Fang AU - Hao Hu AU - Angela M Kaindl Y1 - 2021/05/31 UR - http://jmg.bmj.com/content/early/2021/05/31/jmedgenet-2020-107518.abstract N2 - Background Minichromosomal maintenance (MCM) complex components 2, 4, 5 and 6 have been linked to human disease with phenotypes including microcephaly and intellectual disability. The MCM complex has DNA helicase activity and is thereby important for the initiation and elongation of the replication fork and highly expressed in proliferating neural stem cells.Methods Whole-exome sequencing was applied to identify the genetic cause underlying the neurodevelopmental disease of the index family. The expression pattern of Mcm7 was characterised by performing quantitative real-time PCR, in situ hybridisation and immunostaining. To prove the disease-causative nature of identified MCM7, a proof-of-principle experiment was performed.Results We reported that the homozygous missense variant c.793G&gt;A/p.A265T (g.7:99695841C&gt;T, NM_005916.4) in MCM7 was associated with autosomal recessive primary microcephaly (MCPH), severe intellectual disability and behavioural abnormalities in a consanguineous pedigree with three affected individuals. We found concordance between the spatiotemporal expression pattern of Mcm7 in mice and a proliferative state: Mcm7 expression was higher in early mouse developmental stages and in proliferative zones of the brain. Accordingly, Mcm7/MCM7 levels were detectable particularly in undifferentiated mouse embryonal stem cells and human induced pluripotent stem cells compared with differentiated neurons. We further demonstrate that the downregulation of Mcm7 in mouse neuroblastoma cells reduces cell viability and proliferation, and, as a proof-of-concept, that this is counterbalanced by the overexpression of wild-type but not mutant MCM7.Conclusion We report mutations of MCM7 as a novel cause of autosomal recessive MCPH and intellectual disability and highlight the crucial function of MCM7 in nervous system development.Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as supplemental information. Patient data relevant to the study are included in the article. Further experimental data are available from Ethiraj Ravindran (ethiraj.ravindran@charite.de) and genetic data are available from Hao Hu (huh@cougarlab.org) upon reasonable request. ER -