Rohanizadegan Mersedeh, Abdo Sara M, O'Donnell-Luria Anne, Mihalek Ivana, Chen Peggy, Sanders Marilyn, Leeman Kristen, Cho Megan, Hung Christina, Bodamer Olaf
Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Division of Biochemistry, Faculty of Science, Helwan University, Cairo, Egypt.
Cold Spring Harb Mol Case Stud. 2017 Nov 21;3(6). doi: 10.1101/mcs.a002147. Print 2017 Nov.
Rapid whole-exome sequencing (rWES) is used in critically ill newborn infants to inform about diagnosis, clinical management, and prognosis. Here we report a male newborn infant with hydrops, pancytopenia, and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure-related morbidity and mortality, and lack of diagnosis, we used rWES in the proband and both parents with a turnaround time of 10 business days. rWES returned one maternally inherited, likely pathogenic and one paternally inherited, likely pathogenic variant in , suggestive of a diagnosis of Niemann-Pick disease type C (NPC). Interestingly, a diagnosis of NPC was entertained prior to rWES, but deemed unlikely in light of absent cholesterol storage on liver biopsy and near-normal oxysterol levels in dried blood. The diagnosis of NPC was confirmed on filipin stain in fibroblasts demonstrating defective cholesterol trafficking. NPC is a slowly progressive neurodegenerative disorder that may also affect the liver with overall poor prognosis. It was decided to take the infant off the transplant list and transfer to palliative care, where he died after 4 wk. This case highlights the utility of rWES in an acute clinical setting for several domains of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.
快速全外显子组测序（rWES）用于危重新生儿，以辅助诊断、临床管理及判断预后。本文报告了一名患有水肿、全血细胞减少和急性肝衰竭的男性新生儿，该患儿已被列入肝移植名单。鉴于病情的紧迫性、手术相关的发病率和死亡率以及缺乏诊断结果，我们对先证者及其父母进行了rWES检测，周转时间为10个工作日。rWES检测发现一个母系遗传的、可能致病的变异和一个父系遗传的、可能致病的变异，提示诊断为尼曼-匹克病C型（NPC）。有趣的是，在进行rWES检测之前曾考虑过NPC的诊断，但鉴于肝活检中无胆固醇储存且干血中氧化甾醇水平接近正常，认为可能性不大。通过对成纤维细胞进行菲咯嗪染色，证实了NPC的诊断，显示胆固醇转运存在缺陷。NPC是一种缓慢进展的神经退行性疾病，也可能影响肝脏，总体预后较差。决定将该婴儿从移植名单中移除并转至姑息治疗，其在4周后死亡。该病例突出了rWES在急性临床环境中对精准医学多个领域的作用，包括（1）诊断，（2）预后和结局，（3）管理和治疗，以及（4）资源利用。
