Department of Translational Medicine, Area of Medical Genetics and Genomic Medicine, University of Campinas (UNICAMP), Campinas, SP, Brazil.
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Eur J Hum Genet. 2024 Oct;32(10):1257-1266. doi: 10.1038/s41431-023-01488-5. Epub 2023 Nov 6.
This study describes genomic findings among individuals with both orofacial clefts (OC) and microphthalmia/anophthalmia/coloboma (MAC) recorded in the Brazilian Database on Craniofacial Anomalies (BDCA). Chromosomal microarray analysis (CMA) and Whole Exome Sequencing (WES) were performed in 17 individuals with OC-MAC. Clinical interpretation of molecular findings was based on data available at the BDCA and on re-examination. No copy number variants (CNVs) classified as likely pathogenic or pathogenic were detected by CMA. WES allowed a conclusive diagnosis in six individuals (35.29%), two of them with variants in the CHD7 gene, and the others with variants in the TFAP2A, POMT1, PTPN11, and TP63 genes with the following syndromes: CHARGE, CHD7-spectrum, Branchiooculofacial, POMT1-spectrum, LEOPARD, and ADULT. Variants of uncertain significance (VUS) possibly associated to the phenotypes were found in six other individuals. Among the individuals with VUSes, three individuals presented variants in genes associated to defects of cilia structure and/or function, including DYNC2H1, KIAA0586, WDR34, INTU, RPGRIP1L, KIF7, and LMNA. These results show that WES was the most effective molecular approach for OC-MAC in this cohort. This study also reinforces the genetic heterogeneity of OC-MAC, and the importance of genes related to ciliopathies in this phenotype.
本研究描述了在巴西颅面畸形数据库（BDCA）中记录的同时患有口面裂（OC）和小眼症/无眼症/眼眶裂（MAC）的个体的基因组发现。对 17 名 OC-MAC 患者进行了染色体微阵列分析（CMA）和全外显子组测序（WES）。分子发现的临床解释基于 BDCA 中的数据和重新检查。CMA 未检测到分类为可能致病性或致病性的拷贝数变异（CNVs）。WES 允许在六名个体（35.29%）中进行明确诊断，其中两名个体存在 CHD7 基因中的变异，其他个体存在 TFAP2A、POMT1、PTPN11 和 TP63 基因中的变异，伴有以下综合征：CHARGE、CHD7-谱、Branchiooculofacial、POMT1-谱、LEOPARD 和 ADULT。在其他六个个体中发现了可能与表型相关的意义不明的变异（VUS）。在 VUS 个体中，三名个体存在与纤毛结构和/或功能缺陷相关的基因中的变异，包括 DYNC2H1、KIAA0586、WDR34、INTU、RPGRIP1L、KIF7 和 LMNA。这些结果表明，在该队列中，WES 是 OC-MAC 最有效的分子方法。本研究还加强了 OC-MAC 的遗传异质性，以及与纤毛病相关的基因在这种表型中的重要性。
