Investigation of genetic factors underlying typical orofacial clefts: mutational screening and copy number variation

Abstract

Typical orofacial clefts (OFCs) comprise cleft lip, cleft palate and cleft lip and palate. The complex etiology has been postulated to involve chromosome rearrangements, gene mutations and environmental factors. A group of genes including IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, MSX1 and FGF has been implicated in the etiology of OFCs. Recently, the role of the copy number variations (CNVs) has been studied in genetic defects and diseases. CNVs act by modifying gene expression, disrupting gene sequence or altering gene dosage. The aims of this study were to screen the above-mentioned genes and to investigate CNVs in patients with OFCs. The sample was composed of 23 unrelated individuals who were grouped according to phenotype (associated with other anomalies or isolated) and familial recurrence. New sequence variants in GLI2, MSX1 and FGF8 were detected in patients, but not in their parents, as well as in 200 control chromosomes, indicating that these were rare variants. CNV screening identified new genes that can influence OFC pathogenesis, particularly highlighting TCEB3 and KIF7, that could be further analyzed. The findings of the present study suggest that the mechanism underlying CNV associated with sequence variants may play a role in the etiology of OFC.

A multicentric association study between 39 genes and nonsyndromic cleft lip and palate in a Brazilian population

“…Among the 39 genes analyzed, 16 were associated with NSCLP, including two novel genes, TCEB3 and KIF7, both of which were recently proposed (Simioni et al, 2015). Interestingly, stepwise regression analysis revealed that 15.5% of the NSCLP etiology could be explained by 11 genes: The present study is the first to report association of TCEB3…”

“…This potential association was initially reported based on a copy number study in CL/P individuals (Simioni et al, 2015).…”

“…Although sex-determining region Y-box 7 (SOX7), kinesin family member 7 (KIF7) and transcription elongation factor B (SIII) polypeptide 3 (TCEB3) have not previously been considered candidate genes for oral clefting, they were recently proposed based on a copy number study (Simioni et al, 2015).…”

“…In addition, TCEB3, FGF22, KIF7 and SOX7 were selected based on the results of a previous study involving the BDOC (Simioni et al, 2015). …”

Molecular mechanisms of odontogenesis

“…Ран-ние стадии одонтогенеза регулируют, в частности, такие сигнальные молекулы, как: PAX9, MSX1, фактор роста нервов (nerve growth factor, NGF), костный морфогенети-ческий белок (bone morphogenetic protein, BMP), фактор роста фибробластов (fibroblast growth actor, FGF), продук-ты генов семейства Hedgehog (Sonic Hedgehog, SHH), Distal-less (DLX) и Wingless (WNT). Доказано, что мутации генов MSX1 и PAX9 приводят к селективной аплазии зу-бов [4,6,33,44,46,47], при этом мутации MSX1 также отвечают за развитие некоторых расщелин лица [30,35].…”