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Review
. 2022 Dec 4;13(12):2285.
doi: 10.3390/genes13122285.

Rare CNVs and Known Genes Linked to Macrocephaly: Review of Genomic Loci and Promising Candidate Genes

Giovanna Civitate Bastos  1 , Giovanna Cantini Tolezano  1 , Ana Cristina Victorino Krepischi  1
Affiliations
Review

Rare CNVs and Known Genes Linked to Macrocephaly: Review of Genomic Loci and Promising Candidate Genes

Giovanna Civitate Bastos et al. Genes (Basel). .

Abstract

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.

Keywords: CNV; RALGAPB; RBMS3; TRAPPC9; ZDHHC14; macrocephaly; neurodevelopmental disorders.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Frequency of chromosomes harboring rare de novo <500 kb CNVs detected in 29 macrocephalic patients described in the DECIPHER database.
Figure 2
Figure 2
Map of the loci with CNV syndromes-deletions in red, duplications in blue, or both in purple-associated with microcephaly-represented on the left side of the chromosomes-or macrocephaly-represented on the right side of the chromosomes.
See this image and copyright information in PMC

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This research was funded by São Paulo Research Foundation [FAPESP], grant numbers 2013/080828-1 [CEPID] and 2020/15552-2; and National Council for Scientific and Technological Development [CNPq], grant numbers 157816/2018-4, 305806/2019-0 and 140271/2020-1.

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