De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues

Daphne J. Smits*, Rachel Schot, Cristiana A. Popescu, Kerith Rae Dias, Lesley Ades, Lauren C. Briere, David A. Sweetser, Itaru Kushima, Branko Aleksic, Suliman Khan, Vasiliki Karageorgou, Natalia Ordonez, Frank J.G.T. Sleutels, Daniëlle C.M. van der Kaay, Christine Van Mol, Hilde Van Esch, Aida M. Bertoli-Avella, Tony Roscioli, Grazia M.S. Mancini

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier–Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.

Original languageEnglish
Pages (from-to)949-964
Number of pages16
JournalHuman Genetics
Issue number7
Early online date17 May 2023
Publication statusPublished - Jul 2023

Bibliographical note

Funding Information:
GMSM was supported by a ZonMW Top grand #9127045. The work of LCB and DAS was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Direction under award number U01HG007690 and The Hill Family Fund for the Diagnosis, Management of Rare and Undiagnosed Diseases at Mass General, and the American Institute for Neuro-Integrative Development (AIND) at Mass General Hospital. LA, KRD and TR were supported by funding from the Australian National Health and Medical Research Council to The Centre for Research Excellence in Neurocognitive Disorders (CRE-NCD, Grant No. APP1117394). The content of this paper is solely the responsibility of the authors and does not necessarily represent official views of the NIH.

Funding Information:
We thank the families for participating in this study. We thank Mark Daly (Associate Professor, Department of Psychiatry, Seaver Autism Center for Research and Treatment) and Prof Silvia De Rubeis (Mindich Child Health and Development Institute, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York) for data on the ASC sample cohort. We thank Dr Esther Klingler for providing MCM6 expression data. HVE is a clinical investigator of F.W.O Vlaanderen.

Publisher Copyright:
© 2023, The Author(s).


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