Machado Renato Assis, Martelli-Junior Hercílio, Reis Silvia Regina de Almeida, Küchler Erika Calvano, Scariot Rafaela, das Neves Lucimara Teixeira, Coletta Ricardo D
Department of Oral Diagnosis, School of Dentistry, University of Campinas (FOP), Piracicaba, Brazil.
Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru, Brazil.
Front Cell Dev Biol. 2021 Jul 8;9:638522. doi: 10.3389/fcell.2021.638522. eCollection 2021.
The identification of genetic risk factors for non-syndromic oral clefts is of great importance for better understanding the biological processes related to this heterogeneous and complex group of diseases. Herein we applied whole-exome sequencing to identify potential variants related to non-syndromic cleft palate only (NSCPO) in the multiethnic Brazilian population. Thirty NSCPO samples and 30 sex- and genetic ancestry-matched healthy controls were pooled (3 pools with 10 samples for each group) and subjected to whole-exome sequencing. After filtering, the functional affects, individually and through interactions, of the selected variants and genes were assessed by bioinformatic analyses. As a group, 399 variants in 216 genes related to palatogenesis/cleft palate, corresponding to 6.43%, were exclusively identified in the NSCPO pools. Among those genes are 99 associated with syndromes displaying cleft palate in their clinical spectrum and 92 previously related to cleft lip palate. The most significantly biological processes and pathways overrepresented in the NSCPO-identified genes were associated with the folic acid metabolism, highlighting the interaction between LDL receptor-related protein 6 () and 5-methyltetrahydrofolate-homocysteine methyltransferase () that interconnect two large networks. This study yields novel data on characterization of specific variants and complex processes and pathways related to NSCPO, including many variants in genes of the folate/homocysteine pathway, and confirms that variants in genes related to syndromic cleft palate and cleft lip-palate may cause NSCPO.
鉴定非综合征性口腔裂隙的遗传风险因素对于更好地理解与这类异质性复杂疾病相关的生物学过程至关重要。在此，我们应用全外显子测序来鉴定巴西多民族人群中与仅非综合征性腭裂（NSCPO）相关的潜在变异。将30份NSCPO样本和30份性别及遗传血统匹配的健康对照样本合并（每组3个池，每个池10个样本），并进行全外显子测序。经过筛选后，通过生物信息学分析评估所选变异和基因单独及相互作用的功能影响。作为一个整体，在NSCPO样本池中专门鉴定出了216个与腭发育/腭裂相关基因中的399个变异，占6.43%。在这些基因中，有99个与临床谱显示腭裂的综合征相关，92个先前与唇腭裂相关。在NSCPO鉴定出的基因中最显著富集的生物学过程和途径与叶酸代谢相关，突出了低密度脂蛋白受体相关蛋白6（）和5-甲基四氢叶酸-同型半胱氨酸甲基转移酶（）之间的相互作用，这两个蛋白将两个大网络连接起来。本研究产生了关于NSCPO特定变异以及相关复杂过程和途径特征的新数据，包括叶酸/同型半胱氨酸途径基因中的许多变异，并证实与综合征性腭裂和唇腭裂相关基因的变异可能导致NSCPO。
