Human Genome and Stem-Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo-106 Rua do Matão, São Paulo 05508-090, SP, Brazil.
Genes (Basel). 2022 Dec 4;13(12):2285. doi: 10.3390/genes13122285.
Macrocephaly frequently occurs in single-gene disorders affecting the PI3K-AKT-MTOR pathway; however, epigenetic mutations, mosaicism, and copy number variations (CNVs) are emerging relevant causative factors, revealing a higher genetic heterogeneity than previously expected. The aim of this study was to investigate the role of rare CNVs in patients with macrocephaly and review genomic loci and known genes. We retrieved from the DECIPHER database <500 kb CNVs reported on patients with macrocephaly; in four cases, a candidate gene for macrocephaly could be pinpointed: a known microcephaly gene-, and three genes based on their functional roles-, , and . From the literature review, 28 pathogenic CNV genomic loci and over 300 known genes linked to macrocephaly were gathered. Among the genomic regions, 17 CNV loci (~61%) exhibited mirror phenotypes, that is, deletions and duplications having opposite effects on head size. Identifying structural variants affecting head size can be a preeminent source of information about pathways underlying brain development. In this study, we reviewed these genes and recurrent CNV loci associated with macrocephaly, as well as suggested novel potential candidate genes deserving further studies to endorse their involvement with this phenotype.
巨脑症常发生于影响 PI3K-AKT-MTOR 通路的单基因疾病中；然而，表观遗传突变、嵌合体和拷贝数变异（CNVs）正在成为相关的致病因素，揭示了比预期更高的遗传异质性。本研究旨在探讨罕见 CNVs 在巨脑症患者中的作用，并综述基因组位点和已知基因。我们从 DECIPHER 数据库中检索到 500kb 大小的报告于巨脑症患者的 CNVs；在四个病例中，可以确定一个巨脑症的候选基因：一个已知的小头畸形基因，和三个基于其功能作用的基因， ，和 。通过文献回顾，我们收集了 28 个与巨脑症相关的致病性 CNV 基因组位点和 300 多个已知基因。在这些基因组区域中，17 个 CNV 位点（~61%）表现出镜像表型，即缺失和重复对头部大小有相反的影响。识别影响头部大小的结构变异可以成为了解大脑发育相关通路的重要信息来源。在本研究中，我们综述了这些与巨脑症相关的基因和常见的 CNV 位点，并提出了一些新的潜在候选基因，值得进一步研究以证实它们与该表型的关系。
