INTRODUCTION The gene-environment interaction of the REarranged during Transfection ( RET ) gene with vitamin A in the etiopathogenesis of Hirschsprung disease (HSCR) has been suggested in rodents. The aim of this study was to evaluate vitamin A status in mothers of children with HSCR and to assess its association with pathogenic variants of the RET gene in affected children. METHODS This was a case-control study of stable isotope-based vitamin A measurement stores of mothers of children diagnosed with HSCR (within 8 months from birth, n = 7) and age-matched mothers of normal children (n = 6). Next-generation sequencing of RET exons, along with their upstream promoter region, was performed in the 7 HSCR proband-parent triads to evaluate pathogenic variants. RESULTS Maternal vitamin A stores in the HSCR group was almost 50% that of those in controls, tending toward significance (0.50 ± 0.17 vs 0.89 ± 0.51 μmol/g respectively, P = 0.079). Two novel pathogenic de novo mutations were identified in 2 cases, and a rare single-nucleotide deletion was detected in the 3.5-kb RET upstream region, in a heterozygous state, in all 7 proband-parent triads. Low-penetrance RET haplotypes associated with HSCR were detected in 5 cases. DISCUSSION Mothers with children with HSCR had lower vitamin A liver stores than mothers with normal children, and the children who were affected had HSCR despite having no established pathogenic RET variants. Lower maternal vitamin A status may increase the penetrance of genetic mutations in RET , and vitamin-A mediated gene-environment interactions may underpin some of the etiology of HSCR.

中文翻译：

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母亲维生素 A 状况是儿童先天性巨结肠症的危险因素。

引言 在啮齿动物中，转染期间重排 (RET) 基因与维生素 A 在先天性巨结肠 (HSCR) 发病机制中的基因-环境相互作用已被提出。本研究的目的是评估 HSCR 儿童母亲的维生素 A 状况，并评估其与受影响儿童 RET 基因致病变异的关联。方法 这是一项病例对照研究，对诊断为 HSCR 的儿童母亲（出生后 8 个月内，n = 7）和年龄匹配的正常儿童母亲（n = 6）进行基于稳定同位素的维生素 A 测量储存。在 7 个 HSCR 先证者-亲本三联体中进行了 RET 外显子及其上游启动子区域的新一代测序，以评估致病变异。结果 HSCR 组母体维生素 A 储存量几乎是对照组的 50%，趋于显着（分别为 0.50 ± 0.17 和 0.89 ± 0.51 μmol/g，P = 0.079）。在 2 例病例中鉴定出两种新的致病性从头突变，并且在所有 7 个先证者亲本三联体中，在 3.5 kb RET 上游区域检测到罕见的单核苷酸缺失，处于杂合状态。在 5 例病例中检测到与 HSCR 相关的低外显率 RET 单倍型。讨论 患有 HSCR 儿童的母亲的维生素 A 肝脏储备低于正常儿童的母亲，并且受影响的儿童尽管没有确定的致病性 RET 变异，但患有 HSCR。母体维生素 A 水平较低可能会增加 RET 基因突变的外显率，而维生素 A 介导的基因-环境相互作用可能是 HSCR 某些病因的基础。