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Clinical application of long-read sequencing in newborn genetic screening for congenital adrenal hyperplasia
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DOI：10.3389/fgene.2026.1894466.png)
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Abstract
En 中文
BackgroundScreening for congenital adrenal hyperplasia (CAH) relying solely on 17α-hydroxyprogesterone (17α-OHP) presents limited diagnostic performance; highlighting an urgent need to develop more robust screening strategies for neonates.MethodsWe conducted retrospective and prospective cohort studies to explore the clinical applicability of long-read sequencing (LRS) in CAH genetic testing within primary and secondary newborn screening (NBS) systems; respectively. The retrospective cohort comprised 100; 145 neonates who underwent routine 17α-OHP primary CAH screening at the Fujian Provincial Newborn Screening Center from January 1 to December 31; 2019. Among these infants; 52 full-term screen-positive neonates received further LRS-based CAH genotyping. The prospective cohort enrolled 2; 100 newborns recruited from Fujian Maternity and Child Health Hospital between May 1 and May 31; 2023; who underwent simultaneous 17α-OHP measurement and LRS-mediated CAH genetic analysis.ResultsIn the retrospective cohort; the positive rate of 17α-OHP screening was 0.19% (190/100; 145; 95% CI: 0.17%–0.21%); and five infants were definitively diagnosed with CAH; corresponding to a disease prevalence of 1:20; 029. LRS genotyping successfully identified five neonates harboring pathogenic CYP21A2 mutations consistent with confirmed genetic diagnosis. In this prospective cohort study; two newborns (1/1050) with normal 17α-OHP concentrations were found to carry biallelic pathogenic variants in the CYP21A2 gene. In addition; 88 neonates (4.2%) with normal 17α-OHP levels were found to carry heterozygous CAH-related variants. Among these heterozygotes; 85 individuals harbored CYP21A2 variants; representing 32 distinct genotypes. The calculated carrier frequencies were 1 in 78 for classic CAH and 1 in 40 for non-classic CAH.ConclusionLRS-integrated genetic newborn screening exhibits favorable efficacy for CAH identification. This combined screening modality holds great promise for wide implementation in routine neonatal screening practice.
Keywords:
genetic variation
newborn screening
congenital adrenal hyperplasia
long-read sequencing
CYP21A2
17α-hydroxyprogesterone
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