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

Autor: Smits DJ; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands. d.smits@erasmusmc.nl., Schot R; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands.; Discovery Unit, Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Popescu CA; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., Dias KR; Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, Australia., Ades L; Department of Clinical Genetics, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Specialty of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia., Briere LC; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Sweetser DA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Kushima I; Medical Genomics Center, Nagoya University Graduate School of Medicine, Nagoya, Japan.; Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan., Aleksic B; Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Japan., Khan S; CENTOGENE GmbH, 18055, Rostock, Germany., Karageorgou V; CENTOGENE GmbH, 18055, Rostock, Germany., Ordonez N; CENTOGENE GmbH, 18055, Rostock, Germany., Sleutels FJGT; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands., van der Kaay DCM; Department of Pediatrics, Subdivision of Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands., Van Mol C; Department of Pediatrics, GZ Antwerp, Antwerp, Belgium., Van Esch H; Center for Human Genetics, University Hospitals Leuven, 3000, Leuven, Belgium., Bertoli-Avella AM; CENTOGENE GmbH, 18055, Rostock, Germany., Roscioli T; Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, Australia.; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, Australia., Mancini GMS; Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2023 Jul; Vol. 142 (7), pp. 949-964. Date of Electronic Publication: 2023 May 17.
DOI: 10.1007/s00439-023-02569-7
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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