Supplementary Material for: Importance of Early Genetic Sequencing in Neonates Admitted to NICU with Recurrent Hypernatremia: Results of a Prospective Cohort Study

<b><i>Objectives:</i></b> The genetic characteristics in neonates admitted to the NICU with recurrent hypernatremia remained unknown. We aimed to implement early genetic sequencing to identify possible genetic etiologies, optimize the treatment, and improve the outcome. <b><i>Methods:</i></b> We prospectively performed exome sequencing or targeted panel sequencing on neonates diagnosed with recurrent hypernatremia (plasma sodium ≥150 mEq/L, ≥2 episodes) from January 1, 2016, to June 30, 2020. <b><i>Results:</i></b> Among 22,375 neonates admitted to the NICU, approximately 0.33% (73/22,375) developed hypernatremia. The incidence of hypernatremia &gt;14 days and ≤14 days was 0.03% and 0.3%, respectively. Among 38 neonates who had ≥2 hypernatremia episodes, parents of 28 patients consented for sequencing. Genetic diagnosis was achieved in 25% neonates (7/28). Precision medicine treatment was performed in 85.7% (6/7) of the patients, including hydrochlorothiazide and indomethacin for 57.1% (4/7) with arginine vasopressin receptor 2 (<i>AVPR2</i>) deficiency-associated congenital nephrogenic diabetes insipidus; a special diet of fructose formula for 1 patient with solute carrier family 5 member 1 deficiency-associated congenital glucose-galactose malabsorption (1/7, 14.3%); and kallikrein-inhibiting ointment for 1 patient with serine protease inhibitor of Kazal-type <i>5</i> deficiency-associated Netherton syndrome (1/7, 14.3%). Only hypernatremia onset age (adjusted odds ratio 1.32 [1.01–1.72], <i>p</i> = 0.040) independently predicted the underlying genetic etiology. The risk of a genetic etiology of hypernatremia was 9.0 times higher for neonates with a hypernatremia onset age ≥17.5 days (95% confidence interval, 1.1–73.2; <i>p</i> = 0.038). <b><i>Conclusions:</i></b> Single-gene disorders are common in neonates with recurrent hypernatremia, and &gt;50% of cases are caused by <i>AVPR2</i> deficiency-associated congenital nephrogenic diabetes insipidus. Early genetic testing can aid the diagnosis of unexplained recurrent neonatal hypernatremia and improve therapy and outcome.

研究目的：因反复高钠血症入住新生儿重症监护病房（NICU）的新生儿，其遗传特征此前尚不明确。本研究旨在通过早期基因测序，明确潜在遗传病因，优化治疗方案并改善患儿预后。
研究方法：本研究前瞻性纳入2016年1月1日至2020年6月30日期间确诊为反复高钠血症（血浆钠大于等于150毫当量每升（mEq/L），发作大于等于2次）的新生儿，对其实施外显子测序或靶向基因面板测序。
研究结果：在22375例入住新生儿重症监护病房的新生儿中，约0.33%（73/22375）发生高钠血症。发作时长大于14天与小于等于14天的高钠血症发生率分别为0.03%与0.3%。在38例发作大于等于2次高钠血症的新生儿中，28例患儿家属同意接受测序检测，其中25%（7/28）的新生儿明确了遗传学诊断。7例确诊患儿中85.7%（6/7）接受了精准医学治疗：其中57.1%（4/7）为精氨酸加压素受体2（arginine vasopressin receptor 2，AVPR2）缺陷相关性先天性肾性尿崩症，予以氢氯噻嗪联合吲哚美辛治疗；1例为溶质载体家族5成员1（solute carrier family 5 member 1，SLC5A1）缺陷相关性先天性葡萄糖-半乳糖吸收不良症，予以果糖配方奶特殊饮食治疗（占比14.3%，1/7）；1例为Kazal型5型丝氨酸蛋白酶抑制剂（serine protease inhibitor of Kazal-type 5，SPINK5）缺陷相关性内瑟顿综合征，予以激肽释放酶抑制剂软膏治疗（占比14.3%，1/7）。仅高钠血症发病年龄（校正比值比1.32，95%置信区间1.01至1.72，p=0.040）为潜在遗传病因的独立预测因素。当新生儿高钠血症发病年龄大于等于17.5天时，其存在遗传病因的风险升高9.0倍（95%置信区间1.1至73.2，p=0.038）。
研究结论：单基因遗传病在反复高钠血症新生儿中较为常见，其中超过50%的病例由AVPR2缺陷相关性先天性肾性尿崩症所致。早期基因检测有助于诊断不明原因的新生儿反复高钠血症，并可优化治疗方案、改善患儿预后。