Rare CNVs and Known Genes Linked to Macrocephaly: Review of Genomic Loci and Promising Candidate Genes.
Rare CNVs and Known Genes Linked to Macrocephaly: Review of Genomic Loci and Promising Candidate Genes.
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DOI：
10.3390/genes13122285
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发表时间：
2022-12-04
期刊：
影响因子：
3.5
通讯作者：
Krepischi, Ana Cristina Victorino
中科院分区：
文献类型：
--
作者：
Bastos, Giovanna Civitate;Tolezano, Giovanna Cantini;Krepischi, Ana Cristina Victorino
大头畸形经常发生在影响PI 3 K-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（CNV）是新出现的相关致病因素，揭示了比先前预期更高的遗传异质性。本研究的目的是探讨罕见的CNVs在大头畸形患者中的作用，并回顾基因组位点和已知基因。我们从DECIPHER数据库中重新检索了关于大头畸形患者的<500 kb的CNVs报告;在4个病例中，可以确定一个大头畸形的候选基因：一个已知的小头畸形基因TRAPPC 9，以及三个基于其功能作用的基因RALGAPB、RBMS 3和ZDHHC 14。从文献回顾中，收集了28个致病性CNV基因组位点和300多个已知的基因与大头畸形。在基因组区域中，17个CNV位点（~61%）表现出镜像表型，即缺失和重复对头部大小具有相反的影响。识别影响头部大小的结构变异可能是了解大脑发育途径的重要信息来源。在这项研究中，我们回顾了这些基因和复发性CNV基因座与大头畸形，以及建议新的潜在的候选基因值得进一步研究，以支持他们参与这种表型。
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 de novo <500 kb CNVs reported on patients with macrocephaly; in four cases, a candidate gene for macrocephaly could be pinpointed: a known microcephaly gene–TRAPPC9, and three genes based on their functional roles–RALGAPB, RBMS3, and ZDHHC14. 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.
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