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Objective <p>To explore the use of genomic screening for congenital adrenal hyperplasia (CAH) based on long-read sequencing (LRS), aiming to provide an effective method for LRS-based screening (LRSBCS).</p> Methods <p>All newborns underwent traditional CAH screening via the collection of dried blood spots. We conducted a retrospective clinical study of 73 cases, including 12 confirmed cases of CAH, 18 cases with false-positive biochemical screening results, and 43 healthy newborns as control. Full-length CAH-related genes, including <i>CYP21A2</i>, <i>CYP11B1</i>, <i>CYP17A1</i>, <i>HSD3B2</i>, and <i>STAR</i> were amplified and sequenced on a Sequel II platform (Pacific Biosciences).</p> Results <p>Among the 235,999 newborns, 12 were confirmed to have CAH, based on biochemical and/or genetic testing. The positive-predictive values of the initial and positive recall results were 0.60% (12/1958) and 3.68% (12/326), respectively. The 12 children with CAH were accurately diagnosed using LRSBCS. For LRS, the Bayesian-estimated sensitivity is 96.2% (95% CrI: 80.3%–99.9%) and the specificity is 99.2% (95% CrI: 98.0%–99.9%). Eleven pathogenic variants of <i>CYP21A2</i> were detected, including eight SNVs/indels and three deletions. The most frequent variants were c.293–13&#xa0;C &gt; G (7/11) and c.518T &gt; A (7/11). Furthermore, LRSBCS can directly report the characteristics of gene variants (cis or trans mutations) and effectively distinguish between functional genes and pseudogenes.</p> Conclusions <p>LRSBCS represents a novel molecular screening approach tailored specifically for CAH, demonstrating preliminary feasibility in clinical settings.</p> Clinical trial number <p>Not applicable.</p>

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Newborn genetic screening of congenital adrenal hyperplasia using long-read sequencing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Yuqi Yang,
  • Ying Wang,
  • Bin Zhang,
  • Bin Yu

摘要

Objective

To explore the use of genomic screening for congenital adrenal hyperplasia (CAH) based on long-read sequencing (LRS), aiming to provide an effective method for LRS-based screening (LRSBCS).

Methods

All newborns underwent traditional CAH screening via the collection of dried blood spots. We conducted a retrospective clinical study of 73 cases, including 12 confirmed cases of CAH, 18 cases with false-positive biochemical screening results, and 43 healthy newborns as control. Full-length CAH-related genes, including CYP21A2, CYP11B1, CYP17A1, HSD3B2, and STAR were amplified and sequenced on a Sequel II platform (Pacific Biosciences).

Results

Among the 235,999 newborns, 12 were confirmed to have CAH, based on biochemical and/or genetic testing. The positive-predictive values of the initial and positive recall results were 0.60% (12/1958) and 3.68% (12/326), respectively. The 12 children with CAH were accurately diagnosed using LRSBCS. For LRS, the Bayesian-estimated sensitivity is 96.2% (95% CrI: 80.3%–99.9%) and the specificity is 99.2% (95% CrI: 98.0%–99.9%). Eleven pathogenic variants of CYP21A2 were detected, including eight SNVs/indels and three deletions. The most frequent variants were c.293–13 C > G (7/11) and c.518T > A (7/11). Furthermore, LRSBCS can directly report the characteristics of gene variants (cis or trans mutations) and effectively distinguish between functional genes and pseudogenes.

Conclusions

LRSBCS represents a novel molecular screening approach tailored specifically for CAH, demonstrating preliminary feasibility in clinical settings.

Clinical trial number

Not applicable.