Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary…

Cohort studyChildren (Basel, Switzerland)· Jul 2026

Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort.

Cheng-Yu Lee, Dau-Ming Niu, Chia-Feng Yang, Yann-Jang Chen

Biochemical GeneticsCohort studyQ1IF 2.8

Second-tier exome sequencing confirmed diagnoses in 42.4% of neonates with abnormal newborn screening.

Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort.

Cheng-Yu Lee … Yann-Jang Chen

Children (Basel, Switzerland) · Jul 2026

Background

Whole exome sequencing (whole exome sequencing) has emerged as a clinically valuable second-tier test following abnormal biochemical newborn screening (newborn screening).

Purpose

We aimed to characterize these metrics in a Taiwanese neonatal cohort.

Methods

We retrospectively analyzed 118 consecutive neonates referred to Taipei Veterans General Hospital between August 2021 and August 2022 following abnormal biochemical newborn screening.

n = 61

42.4%

Results

42.4%

Molecular testing confirmed a true genetic diagnosis in about 4 in 10 referred neonates.

n = 61

More results

Five participants (4.2%) harbored pathogenic/likely pathogenic variants in ACMG secondary findings v3.3 genes ( TTN , LDLR , PTEN , RYR1 , TP53 ).

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).

More results

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.

“

Conclusion · 1 of 2

Second-tier whole exome sequencing substantially improves diagnostic precision, discriminating confirmed diagnoses from carrier, pseudodeficiency, and biochemical false-positive states.

Conclusion · 2 of 2

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.

Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort.

Second-Tier Whole Exome Sequencing Following Abnormal Newborn Screening: Diagnostic Yield, Secondary Findings, and Carrier Burden in a Taiwanese Neonatal Cohort.

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