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 <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.

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice

“…NIBP syndrome is one type of NS-ARID, caused by autosomal recessive variations and mutations of TRAPPC9 [24], leading to a deficiency of functional TRAPPC9. Patients carrying homozygous or compound heterozygous mutations of TRAPPC9 genes display distinctive clinical phenotypes mainly including neurological manifestations such as severe intellectual disability predominating on speech, behavioral anomalies, motor development, and variable post-natal microcephaly [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Some patients present with clinical features of autism spectrum disorder [32,33,65,66].…”

“…Mutations in TRAPPC9 are associated with non-syndromic autosomal recessive intellectual disability (NS-ARID), assigned as "Intellectual Disability-Obesity-Brain Malformations-Facial Dysmorphism Syndrome" and "Intellectual developmental disorder, autosomal recessive 13" (OMIM #613192), and abbreviated as NIBP syndrome [24,28]. Loss-of-function TRAPPC9 mutations manifest microcephaly, intellectual disability, and obesity in patients [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Magnetic resonance imaging in affected individuals with NIBP syndrome has revealed reduced cerebral white matter volume with sulcal enlargement, thinning of the corpus callosum, and mild cerebellar volume loss [29][30][31].…”

Macrocephaly and Finger Changes: A Narrative Review

“…Glomus tumors of the fingers (benign neoplasms that arise from the glomus body, a specialized thermoregulatory shunt which is concentrated in the fingers and toes) are associated with neurofibromatosis and their appearance is determined by the loss of neurofibromin function [126,127]. In neurofibromatosis type 1 (NF1), a common AD syndrome with variable expressivity, MC may be due to ME and is frequently associated to a short stature [9]. Fingers in NF1 may be affected by neurofibromas, glomus tumors, bone enlargement, pseudarthrosis of the forearm or hand bones, etc.…”

“…ME is caused by the abnormal size or number of dysfunctional neurons and/or glia. Brain development is controlled by multiple signaling pathways involved in proliferation, migration, and organization of neurons and glia (mTOR, Ras/MAPK, and SHH pathways) [4,8,9]. Copy number variations (CNVs), which are an important source of genetic variability, can also be considered causative factors of ME, together with mosaicism and epigenetic mutations [8,9].…”

“…Brain development is controlled by multiple signaling pathways involved in proliferation, migration, and organization of neurons and glia (mTOR, Ras/MAPK, and SHH pathways) [4,8,9]. Copy number variations (CNVs), which are an important source of genetic variability, can also be considered causative factors of ME, together with mosaicism and epigenetic mutations [8,9]. Usually, ME is associated with developmental disabilities and is often more syndromic than MC [10].…”