Marseille Medical Genetics (MMG) U1251, Aix Marseille Université, INSERM, 13005, Marseille, France.
Institute of Functional Genomics (IGF), University of Montpellier, CNRS, INSERM, LabEx ICST, Montpellier, France.
J Transl Med. 2023 Feb 28;21(1):160. doi: 10.1186/s12967-023-03994-y.
Recent studies have shown the implication of the ROBO-SLIT pathway in heart development. Within this study, we aimed to further assess the implication of the ROBO and SLIT genes mainly in bicuspid aortic valve (BAV) and other human congenital heart defects (CHD).
We have analyzed a cohort of singleton exome sequencing data comprising 40 adult BAV patients, 20 pediatric BAV patients generated by the Pediatric Cardiac Genomics Consortium, 10 pediatric cases with tetralogy of Fallot (ToF), and one case with coarctation of the aorta. A gene-centered analysis of data was performed. To further advance the interpretation of the variants, we intended to combine more than 5 prediction tools comprising the assessment of protein structure and stability.
A total of 24 variants were identified. Only 4 adult BAV patients (10%) had missense variants in the ROBO and SLIT genes. In contrast, 19 pediatric cases carried variants in ROBO or SLIT genes (61%). Three BAV patients with a severe phenotype were digenic. Segregation analysis was possible for two BAV patients. For the homozygous ROBO4: p.(Arg776Cys) variant, family segregation was consistent with an autosomal recessive pattern of inheritance. The ROBO4: c.3001 + 3G > A variant segregates with the affected family members. Interestingly, these variants were also found in two unrelated patients with ToF highlighting that the same variant in the ROBO4 gene may underlie different cardiac phenotypes affecting the outflow tract development.
Our results further reinforce the implication of the ROBO4 gene not only in BAV but also in ToF hence the importance of its inclusion in clinical genetic testing. The remaining ROBO and SLIT genes may be screened in patients with negative or inconclusive genetic tests.
最近的研究表明 ROBO-SLIT 通路在心脏发育中具有重要意义。在本研究中，我们旨在进一步评估 ROBO 和 SLIT 基因在二叶式主动脉瓣（BAV）和其他人类先天性心脏病（CHD）中的作用。
我们分析了一组由 40 名成人 BAV 患者、20 名儿科心脏基因组学联盟生成的儿科 BAV 患者、10 名法洛四联症（ToF）患儿和 1 名主动脉缩窄患者的单倍体外显子测序数据。对数据进行了以基因为中心的分析。为了进一步推进对变体的解释，我们打算结合包括评估蛋白质结构和稳定性在内的 5 种以上的预测工具。
共发现 24 个变体。只有 4 名成人 BAV 患者（10%）在 ROBO 和 SLIT 基因中存在错义变体。相比之下，19 名儿科患者在 ROBO 或 SLIT 基因中携带变体（61%）。3 名具有严重表型的 BAV 患者为双基因。两名 BAV 患者的分离分析是可行的。对于纯合 ROBO4：p.（Arg776Cys）变体，家系分离符合常染色体隐性遗传模式。ROBO4：c.3001 + 3G > A 变体与受影响的家族成员一起分离。有趣的是，这些变体也在两名患有 ToF 的无关联患者中被发现，这表明 ROBO4 基因中的相同变体可能导致影响流出道发育的不同心脏表型。
我们的结果进一步强调了 ROBO4 基因不仅在 BAV 中，而且在 ToF 中都具有重要意义，因此其纳入临床基因检测非常重要。对于基因检测阴性或不确定的患者，可以进一步筛选其他 ROBO 和 SLIT 基因。
