Meng Linyan, Pammi Mohan, Saronwala Anirudh, Magoulas Pilar, Ghazi Andrew Ray, Vetrini Francesco, Zhang Jing, He Weimin, Dharmadhikari Avinash V, Qu Chunjing, Ward Patricia, Braxton Alicia, Narayanan Swetha, Ge Xiaoyan, Tokita Mari J, Santiago-Sim Teresa, Dai Hongzheng, Chiang Theodore, Smith Hadley, Azamian Mahshid S, Robak Laurie, Bostwick Bret L, Schaaf Christian P, Potocki Lorraine, Scaglia Fernando, Bacino Carlos A, Hanchard Neil A, Wangler Michael F, Scott Daryl, Brown Chester, Hu Jianhong, Belmont John W, Burrage Lindsay C, Graham Brett H, Sutton Vernon Reid, Craigen William J, Plon Sharon E, Lupski James R, Beaudet Arthur L, Gibbs Richard A, Muzny Donna M, Miller Marcus J, Wang Xia, Leduc Magalie S, Xiao Rui, Liu Pengfei, Shaw Chad, Walkiewicz Magdalena, Bi Weimin, Xia Fan, Lee Brendan, Eng Christine M, Yang Yaping, Lalani Seema R
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Baylor Genetics Laboratory, Houston, Texas.
JAMA Pediatr. 2017 Dec 4;171(12):e173438. doi: 10.1001/jamapediatrics.2017.3438.
While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.
To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.
DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children's Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.
Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.
The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling.
Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.
虽然先天性畸形和遗传疾病是婴儿早期死亡的主要原因，但据我们所知，单基因疾病在这一群体中的作用尚不确定。
确定临床外显子组测序在危重症婴儿中的诊断率及应用情况。
设计、地点和参与者：对2011年12月至2017年1月期间在得克萨斯州休斯敦的德克萨斯儿童医院住院的278名出生后100天内的非亲属婴儿进行了临床外显子组测序。外显子组测序类型包括先证者外显子组、三联体外显子组和关键三联体外显子组，后者是一种针对重症婴儿的快速基因组检测方法。
检测指征、临床外显子组测序的诊断率、周转时间、分子学发现、诊断时的患者年龄，以及一组疑似患有遗传疾病的危重症婴儿的医疗管理效果。
参与研究的婴儿的平均（标准误）年龄为28.5（1.7）天；其中，接受先证者外显子组测序的婴儿的平均（标准误）年龄为29.0（2.2）天，三联体外显子组为31.5（3.9）天，关键三联体外显子组为22.7（3.9）天。外显子组测序的临床指征包括一系列医疗问题。总体而言，通过临床外显子组测序在102名婴儿（36.7%）中实现了分子诊断，心血管异常的诊断率相对较低。该诊断影响了53名婴儿（52.0%）的医疗管理，并对知情的护理调整、新专科护理的启动、药物/饮食调整以及特定患者的进一步挽救生命程序产生了重大影响。关键三联体外显子组测序在63名婴儿中的32名（50.8%）中发现了分子诊断，平均（标准误）诊断年龄为33.1（5.6）天，平均（标准误）周转时间为13.0（0.4）天。32名患者中的23名（71.9%）的诊断改变了临床护理。与接受常规外显子组检测的组相比，接受关键三联体外显子组测序的组的诊断率、诊断时的患者年龄和医疗效果有显著差异。对于死亡婴儿（n = 81），通过外显子组测序在39名（48.1%）中分子诊断出遗传疾病，这对复发风险咨询有影响。
外显子组测序是新生儿和儿科重症监护病房中对疑似单基因疾病的危重症婴儿进行诊断评估的有力工具，其应用对临床决策有显著影响。
