HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.
Cold Spring Harb Mol Case Stud. 2020 Feb 3;6(1). doi: 10.1101/mcs.a004531. Print 2020 Feb.
Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for p.H63D. He also has a very rare p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis.
尽管囊性纤维化 (CF) 患者的基因型和环境相同，但他们的疾病发病和/或严重程度经常存在差异。我们推测，基因组变异（修饰和/或药物基因组学变异）可能解释了这些临床差异。从威斯康星州新生儿 CF 筛查随机临床试验 (RCT) 纳入的患者队列中，我们鉴定了两名兄弟，他们在儿童时期表现出不同的肺部疾病进程，一个较轻，另一个比平均水平更严重，而第三个哥哥也患有严重的肺部疾病。采集白细胞作为 DNA 的来源，并进行全基因组测序 (WGS)。使用内部开发的信息学工具鉴定和分析变体。在儿童时期，兄弟俩的肺部疾病发病和严重程度存在明显差异。肺部疾病较轻的弟弟是 p.H63D 纯合子。他还携带一种非常罕见的 p.D238N 变体，可能会影响慢性肺部感染期间的宿主-病原体相互作用。在兄弟姐妹之间还发现了其他有意义的变异。药物基因组学发现与中间、最严重受影响的哥哥对常见 CF 治疗的不良预后一致。我们得出结论，CF 患者的兄弟姐妹之间存在基因组变异是预期的。可变的肺部疾病严重程度可能与作为遗传修饰因子和/或药物基因组学因素的差异有关，但需要进行大型队列研究来评估这一假设。
