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.

微型染色体维持 (MCM) 复合物在 DNA 复制过程中充当 DNA 解旋酶，从而调节细胞周期进程和增殖。此外，MCM复合体成分定位于中心体并在纤毛发生中发挥独立作用。编码 MCM 成分和其他 DNA 复制因子的基因的致病性变异与生长和发育障碍（如迈耶-戈林综合征和塞克尔综合征）有关。三重外显子组/基因组测序鉴定出相同的 de novo MCM6错义变异 p.(Cys158Tyr) 在两个不相关的个​​体中出现，表现出重叠的表型，包括子宫内生长迟缓、身材矮小、先天性小头畸形、内分泌特征、发育迟缓和泌尿生殖系统异常。已鉴定的变体影响 MCM6 锌指特征中的锌结合半胱氨酸。该结构域，特别是半胱氨酸残基，对于 MCM 复合物二聚化和解旋酶活性的诱导至关重要，表明该变体对 DNA 复制具有有害影响。来自两个受影响个体的成纤维细胞在纤毛发生和细胞增殖方面都显示出缺陷。我们还利用 de novo MCM6追踪到了三个不相关的个​​体寡核苷酸结合（OB）折叠域中的变异体，呈现出可变的（神经）发育特征，包括自闭症谱系障碍、发育迟缓和癫痫。综上所述，我们的研究结果表明MCM6的新变异与神经发育障碍有关。与锌结合残基相关的临床特征和功能缺陷类似于在与其他 MCM 成分和 DNA 复制因子相关的综合征中观察到的临床特征和功能缺陷，而从头 OB 折叠结构域错义变异可能与更多可变的神经发育表型相关。这些数据鼓励在 NDD 诊断库中考虑MCM6变异。