Análise cromossômica por microarranjos aplicada à identificação de alterações genômicas em pacientes com fissura lábio palatina

Abstract

Non-syndromic orofacial clefts (OFC) consist of craniofacial malformations characterized by the presence of abnormal spaces or gaps in the upper lip, alveolus and/or palate, which may have effects on speech, hearing, appearance and cognition, as well as long-term adverse outcomes health and social integration. Despite the various environmental agents already identified, genetic susceptibility is in fact the main component of the etiology of non-syndromic OFC. However, despite decades of genetic research and the different types of genetic studies, it is still unclear exactly how many genes can control the risk or how they act to influence the risk of orofacial clefts. Large-scale studies of the entire genome using high throughput technologies as comparative Chromosomal Microarray Analysis (CMA) have been shown to be an important tool in the study of complex and heterogeneous diseases, since it allows mapping of wide structural variations of a reference genome, including deletions and duplications, collectively referred to as Copy Number Variations (CNVs). Thus, the present study aimed to identify and describe rare CNVs in non-syndromic OFC patients using CMA to explore the implication of overlapping CNV genes for the genetic etiology of OFC. Five rare CNVs were identified in five OFC patients: a 220kb deletion located in the 1p12 region, overlapping the three GDAP2, WDR3, SPAG17 genes; a 326kb doubling in the 3p22.3 region, spanning the CCR4 and GLB1 genes and the doubling in the 4q32.3, 10p14, 15q13.3 regions overlapping the SPOCK3, CELF2, CHRNA7 genes, respectively. Only the 440kb duplication on chromosome 15 involving the cholinergic neuronal nicotinic receptor gene, alpha 7 polypeptide (CHRNA7) was previously described in a patient with OFC phenotype. All evidenced genes participate in cellular events essential to the embryological development of the lip and palate and, therefore, may represent potential candidate genes of the patients studied.