The purpose of this study is to describe a Mendelian disorder of DNA damage repair. Phenotypic delineation of two families, one new and one previously published, with overlapping dysmorphic and neurodevelopmental features was undertaken. Functional characterization of DNA damage repair in fibroblasts obtained from the index individuals in each of the two families was pursued. We present new evidence of a distinct disorder caused by biallelic truncating variants in ZNF668 comprising microcephaly, growth deficiency, severe global developmental delay, brain malformation, and distinct facial dysmorphism. DNA damage repair defect was observed in fibroblasts of affected individuals. ZNF668 deficiency in humans results in a recognizable autosomal recessive disorder, which we propose to name ZNF668-related ZMAND (ZNF668-related brain malformation, microcephaly, abnormal growth, neurodevelopmental delay, and dysmorphism). Our results add to the growing list of Mendelian disorders of the DNA damage repair machinery.

本研究的目的是描述 DNA 损伤修复的孟德尔疾病。对两个家族进行了表型描述，一个是新的，一个是以前发表的，具有重叠的畸形和神经发育特征。对从两个家族中的每一个中的索引个体获得的成纤维细胞中的 DNA 损伤修复进行了功能表征。我们提出了由ZNF668中的双等位基因截断变异引起的明显疾病的新证据，包括小头畸形、生长缺陷、严重的整体发育迟缓、脑畸形和明显的面部畸形。在受影响个体的成纤维细胞中观察到 DNA 损伤修复缺陷。人类 ZNF668 缺乏导致可识别的常染色体隐性遗传病，我们建议将其命名为ZNF668-相关的 ZMAND（与 ZNF668 相关的脑畸形、小头畸形、生长异常、神经发育迟缓和畸形）。我们的结果添加到越来越多的 DNA 损伤修复机制的孟德尔疾病列表中。