Journal Article
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
Human Genetics · Vol. 142, Issue 7 · pp. 949-964 · 2023
Abstract
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.