Children · Published 2026-07-23 · DOI 10.3390/children13080977
Cheng-Yu Lee, Dau-Ming Niu, Chia-Feng Yang, Yann-Jang Chen
<b>Background/Objectives:</b> Whole exome sequencing (WES) has emerged as a clinically valuable second-tier test following abnormal biochemical newborn screening (NBS). However, population-specific data on diagnostic yield, secondary findings (SFs), and exome-wide carrier burden remain scarce in East Asian neonates, particularly since the release of the ACMG SF v3.3 gene list. We aimed to characterize these metrics in a Taiwanese neonatal cohort. <b>Methods:</b> We retrospectively analyzed 118 consecutive neonates referred to Taipei Veterans General Hospital between August 2021 and August 2022 following abnormal biochemical NBS. WES was performed on the Illumina NovaSeq 6000 platform; variants were classified per the 2015 ACMG/AMP framework and re-evaluated under ACMG SF v3.3. Referral categories comprised lysosomal storage diseases (<i>n</i> = 61), amino acid disorders (<i>n</i> = 38), fatty acid oxidation disorders (<i>n</i> = 13), and organic acid disorders (<i>n</i> = 6). <b>Results:</b> Fifty neonates (42.4%) received confirmed molecular diagnoses and 45 (38.1%) were carriers (combined molecular resolution 80.5%). Five participants (4.2%) harbored pathogenic/likely pathogenic variants in ACMG SF v3.3 genes (<i>TTN</i>, <i>LDLR</i>, <i>PTEN</i>, <i>RYR1</i>, <i>TP53</i>). Incidental findings occurred in 51.7%, and at least one recessive-carrier variant was detected in 99.2% (mean 4.15 per individual; median 4). The Taiwanese-specific c.639+919G>A cardiac Fabry variant accounted for 24/25 confirmed male Fabry cases, and the p.Gly576Ser pseudodeficiency allele confounded all suspected Pompe cases. <b>Conclusions:</b> Second-tier WES substantially improves diagnostic precision, discriminating confirmed diagnoses from carrier, pseudodeficiency, and biochemical false-positive states. The high carrier burden and incidental-finding rate underscore the importance of comprehensive pre- and post-test genetic counseling in East Asian neonatal genomic programs.
Abstract from DOAJ. Public domain (CC0 1.0).
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Lee, C., Niu, D., Yang, C., et al. (2026). Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort. Children. https://doi.org/10.3390/children13080977