Wyatt MacKenzie, Quinn Alexandra, Shade Lincoln, McGarry Meghan
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98105, USA.
Center for Respiratory Biology and Therapeutics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
Int J Neonatal Screen. 2025 Jul 30;11(3):60. doi: 10.3390/ijns11030060.
An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS who do not meet the diagnostic criteria for CF (two CF-causing variants and/or sweat chloride > 60 mmol/L). This indeterminate diagnosis is called cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive, inconclusive diagnosis (CFSPID). CRMS/CFSPID occurs when it is not clearly known whether variants are disease-causing. In 2024, the CFTR2 classification of many variants was changed from unknown significance to either CF-causing variants or variants of varying clinical consequences (VVCCs). We conducted a meta-analysis of CRMS/CFSPID cases from manuscripts to describe how the diagnoses would change using two different variant panels: (1) only CF-causing variants (Panel) and (2) CF-causing variants and VVCCs (Panel). Using the Panel, 8.7% had two CF-causing variants (reclassified as CF), while 91.3% had less than two CF-causing variants (reclassified as Undetected). Using the Panel, 51.4% had either two VVCCs or one VVCC with one CF-causing variant detected (reclassified as CRMS/CFSPD), 39.9% had less than two CF-causing variants detected (reclassified as Undetected), and 8.7% had two CF-causing variants (reclassified as CF). In conclusion, using the updated CFTR2 classification of variants significantly decreases the number of children with CRMS/CFSPID and gives a definitive diagnosis of CF to some children while not detecting as many children who are unlikely to develop CF.
囊性纤维化（CF）新生儿筛查（NBS）的一个意外后果是，发现一些NBS结果呈阳性但不符合CF诊断标准（两个导致CF的变异和/或汗液氯化物>60 mmol/L）的婴儿。这种不确定的诊断被称为囊性纤维化跨膜传导调节因子（CFTR）相关代谢综合征（CRMS）或CF筛查阳性、诊断不确定（CFSPID）。当不清楚变异是否致病时，就会出现CRMS/CFSPID。2024年，许多变异的CFTR2分类从不明意义改为导致CF的变异或具有不同临床后果的变异（VVCC）。我们对手稿中的CRMS/CFSPID病例进行了荟萃分析，以描述使用两种不同的变异组如何改变诊断：（1）仅导致CF的变异（组1）和（2）导致CF的变异和VVCC（组2）。使用组1时，8.7%有两个导致CF的变异（重新分类为CF），而91.3%有少于两个导致CF的变异（重新分类为未检测到）。使用组2时，51.4%有两个VVCC或检测到一个VVCC和一个导致CF的变异（重新分类为CRMS/CFSPD），39.9%检测到少于两个导致CF的变异（重新分类为未检测到），8.7%有两个导致CF的变异（重新分类为CF）。总之，使用更新后的CFTR2变异分类显著减少了CRMS/CFSPID儿童的数量，并为一些儿童给出了明确的CF诊断，同时未检测到那么多不太可能患CF的儿童。
