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Cited by 6Sexual Differentiation and DisordersMetabolism and Genetic DisordersAdrenal Hormones and Disorders

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Assessment of Long-Read Sequencing-Based Congenital Adrenal Hyperplasia Genotyping Assay for Newborns in Fujian, China

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Wang, Xudong, Lu, Xingxiu, Zheng, Faming, Lin, Kun, Liao, Minjuan, Dong, Yi, Chen, Tiantian, He, Ying, Lu, Mei, Chen, Jing, Li, Yanfang, Zhou, Yulin·2025·International Journal of Neonatal Screening
DOI 10.3390/ijns11010022PMC PMC11942758
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Abstract

Long-read sequencing (LRS) provides comprehensive genetic information, but research of LRS applied to congenital adrenal hyperplasia (CAH) newborn screening is limited. This study aimed to evaluate the clinical utility of LRS in genetic diagnosis and second-tier newborn screening. Neonates born between January 2017 and December 2022 in Fujian, China, were recruited for biochemical and LRS-based genetic screening assay. The LRS covers the entire gene regions and exon–intron boundary regions for CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR. In this retrospective study, 1,774,555 newborns received 17α-OHP screening, yielding a screening positive rate of 0.20%. Of these high-risk neonates, 3411 were successfully recalled for re-evaluation. Finally, 66 neonates were diagnosed with CAH, with a positive predictive value of 28.82%. Based on this data, the overall prevalence of CAH in Fujian was estimated to be 1:26,883. LRS was performed on 57 neonates with 21-hydroxylase deficiency (21-OHD) and 109 variant alleles were identified. The c.293-13C>G variant (31.19%) was the most prevalent in Fujian. Additionally, 647 neonates with suspected positive results were genotyped, and 41 were identified as carriers, with carrier frequencies of 1:18 for CYP21A2, 1:162 for HSD3B2, and 1:324 for CYP17A1 in Xiamen. Therefore, LRS can provide comprehensive genotypes in approximately 1.5 days at a cost of less than $20 USD per sample, and effectively improve screening efficiency, reduce anxiety of parents during newborn screening (NBS), and shorten the time to referral of CAH patients (approximately 10 days). Such a combined screening strategy is worthy to be recommended for NBS programs in the future.

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Figure 1 Assessment of long-read sequencing-based CAH genotyping assay for CAH newborn screening program: (A) assessment of long-read sequencing assay in genetic diagnosis of CAH patients; (B) assessment of long-read sequencing assay in CAH second-tier screening in Xiamen City.
Figure 1 Assessment of long-read sequencing-based CAH genotyping assay for CAH newborn screening program: (A) assessment of long-read sequencing assay in genetic diagnosis of CAH patients; (B) assessment of long-read sequencing assay in CAH second-tier screening in Xiamen City.CC BY · PubMed Central
Figure 2 Positions of multiplex PCR-specific primer pairs targeting CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR in LRS-based genotyping assay.
Figure 2 Positions of multiplex PCR-specific primer pairs targeting CYP21A2, CYP11B1, CYP17A1, HSD3B2, and StAR in LRS-based genotyping assay.CC BY · PubMed Central
Figure 3 Incidence of CAH and Variants Distribution in Fujian Province: (A) incidence of CAH in 6 newborn screening centers from Fujian Province; (B) distribution of variants identified in 58 CAH patients from Fujian Province.
Figure 3 Incidence of CAH and Variants Distribution in Fujian Province: (A) incidence of CAH in 6 newborn screening centers from Fujian Province; (B) distribution of variants identified in 58 CAH patients from Fujian Province.CC BY · PubMed Central
Figure 4 IGV plots of LRS results showing variations of CAH genes: (A) sample ND007 with CYP21A2 SNV/indels; (B) sample PT001 with CYP21A2 SNV and gene deletion; (C) sample QZ032 with homozygous CYP21A2 deletions; (D) sample QZ030 with compound heterozygous CYP21A2 deletions; (E) sample XM001 with CYP21A2 SNVs and gene deletion; (F) sample LY010 with CYP21A2 gene deletion and complex variations.
Figure 4 IGV plots of LRS results showing variations of CAH genes: (A) sample ND007 with CYP21A2 SNV/indels; (B) sample PT001 with CYP21A2 SNV and gene deletion; (C) sample QZ032 with homozygous CYP21A2 deletions; (D) sample QZ030 with compound heterozygous CYP21A2 deletions; (E) sample XM001 with CYP21A2 SNVs and gene deletion; (F) sample LY010 with CYP21A2 gene deletion and complex variations.CC BY · PubMed Central
Figure 5 Comparison of different screening strategies in CAH newborn screening: (A) traditional newborn screening strategy in Xiamen City; (B) combined biochemical and genetic screening strategy. ACTH, adrenocorticotropic hormone; MLPA, multiplex ligation-dependent probe amplification; “at least 2 tests for positive”, at least 2 tests for positive in 17-OHP screening assay can be determined as screening positive.
Figure 5 Comparison of different screening strategies in CAH newborn screening: (A) traditional newborn screening strategy in Xiamen City; (B) combined biochemical and genetic screening strategy. ACTH, adrenocorticotropic hormone; MLPA, multiplex ligation-dependent probe amplification; “at least 2 tests for positive”, at least 2 tests for positive in 17-OHP screening assay can be determined as screening positive.CC BY · PubMed Central

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Metadata

Authors
Wang, X., Lu, X., Zheng, F., Lin, K., Liao, M., Dong, Y., Chen, T., He, Y., Lu, M., Chen, J., Li, Y., & Zhou, Y.
Affiliations
  • Xiamen University (CN)
  • Quanzhou Women and Children's Hospital (CN)
  • Putian University (CN)
  • Fujian Medical University (CN)
  • Screening Center of Neonatal Genetic Metabolic Disease, Ningde Maternity and Child Health Care Hospital, Ningde 352100, China
  • Zhangzhou Newborn Screening Center, Zhangzhou Maternity and Child Care Hospital, Zhangzhou 363000, China
Corresponding author
Wang, Xudong
ORCID
Venue
International Journal of Neonatal Screening
Publisher
MDPI AG
Published
2025-03-13
Volume
11
Issue
1
Pages
22
ISSN
2409-515X (ISSN-L)
DOI
10.3390/ijns11010022
PMC
PMC11942758
OpenAlex
W4408409007
Cited by
6
References
35
Citations by year
2026: 4 · 2025: 2
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Neonatal Screening (publishedVersion, cc-by)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82101824, 3502Z20227296, 3502Z20224014, 2021CXB025)
  • Xiamen Natural Science Foundation (82101824, 3502Z20227296, 3502Z20224014, 2021CXB025)
  • General Science and Technology Project of Xiamen, China (82101824, 3502Z20227296, 3502Z20224014, 2021CXB025)
  • Fujian Provincial Health Technology Project (82101824, 3502Z20227296, 3502Z20224014, 2021CXB025)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
congenital adrenal hyperplasia, long-read sequencing, newborn screening, 21-hydroxylase deficiency, CYP21A2, CYP11B1, CYP17A1, HSD3B2, stars, 17-hydroxyprogesterone, carrier frequency, variant allele frequency, Fujian

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