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

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 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
• macrocephaly
• neurodevelopmental disorders
• <i>TRAPPC9</i>
• <i>RALGAPB</i>
• <i>RBMS3</i>