Kids Heart Research, The Children's Hospital at Westmead, Sydney, Australia; Heart Centre for Children, The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia.
Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, Australia.
Am Heart J. 2018 Jul;201:33-39. doi: 10.1016/j.ahj.2018.03.021. Epub 2018 Apr 5.
Up to 20% of children with congenital heart disease (CHD) undergoing cardiac surgery develop neurodevelopmental disabilities (NDD), with some studies reporting persistent impairment. Recent large-scale studies have demonstrated shared genetic mechanisms contributing to CHD and NDD. In this study, a targeted approach was applied to assess direct clinical applicability of this information.
A gene panel comprising 148 known CHD and/or NDD genes was used to sequence 15 patients with CHD + NDD, 15 patients with CHD, and 15 healthy controls. The number and types of variants between the 3 groups were compared using Poisson log-linear regression, and the SNP-set (Sequence) Kernel Association Test-Optimized was used to conduct single-gene and gene-pathway burden analyses.
A significant increase in rare (minor allele frequency < 0.01) and novel variants was identified between the CHD + NDD cohort and controls, P < .001 and P = .001, respectively. There was also a significant increase in rare variants in the CHD cohort compared with controls (P = .04). Rare variant burden analyses implicated pathways associated with "neurotransmitters," "axon guidance," and those incorporating "RASopathy" genes in the development of NDD in CHD patients.
These findings suggest that an increase in novel and rare variants in known CHD and/or NDD genes is associated with the development of NDD in patients with CHD. Furthermore, burden analyses point toward rare variant burden specifically in pathways related to brain development and function as contributors to NDD. Although promising variants and pathways were identified, further research, utilizing whole-genome approaches, is required prior to demonstrating clinical utility in this patient group.
多达 20%接受心脏手术的先天性心脏病 (CHD) 患儿会出现神经发育障碍 (NDD)，一些研究报告称存在持续性损害。最近的大规模研究表明，CHD 和 NDD 存在共同的遗传机制。在这项研究中，采用了靶向方法来评估该信息的直接临床适用性。
使用包含 148 个已知 CHD 和/或 NDD 基因的基因面板，对 15 名 CHD+NDD 患儿、15 名 CHD 患儿和 15 名健康对照进行测序。使用泊松对数线性回归比较 3 组之间的变异数量和类型，并使用 SNP 集（序列）核关联测试优化进行单基因和基因途径负担分析。
CHD+NDD 组与对照组之间罕见（次要等位基因频率 <0.01）和新变异的数量显著增加，分别为 P <0.001 和 P =0.001。与对照组相比，CHD 组的罕见变异数量也显著增加（P =0.04）。罕见变异负担分析表明，与 CHD 患者 NDD 发育相关的途径包括“神经递质”、“轴突导向”和包含“RASopathy”基因的途径。
这些发现表明，已知 CHD 和/或 NDD 基因中新的罕见变异的增加与 CHD 患儿 NDD 的发生有关。此外，负担分析表明，与大脑发育和功能相关的途径中的罕见变异负担可能是 NDD 的促成因素。虽然确定了有前途的变异和途径，但在该患者群体中证明临床实用性之前，还需要利用全基因组方法进行进一步研究。
