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Building a Targeted LRS Panel for Newborn CAH Screening

  • Jan 20
  • 2 min read

How Long-Read Sequencing resolves the CYP21A2-TNXB highly homologous pseudogene challenge and enhances first-tier screening.

Introduction: The Evolution of Newborn Screening


Compared to traditional biochemical assays, Genetic Newborn Screening (NBS) offers a distinct advantage: clearer results, reduced unnecessary follow-up, and the ability to detect conditions that lack early-stage biochemical markers. Thanks to advancements in sequencing technology, laboratories can now screen for hundreds of conditions in a single assay with reduced costs. While many Next-Generation Sequencing (NGS)-based screening panels (including our NBSure™ NGS service) are commercially available, standard short-read NGS faces significant limitations regarding specific genes and variant types.


The Challenge: The CYP21A2 "Dark Region"


One of the challenges for standard NGS panels lies in the CYP21A2-TNXB region. Mutations in CYP21A2 are responsible for 90% of Congenital Adrenal Hyperplasia (CAH) cases (21-hydroxylase deficiency).

Current screening methods often fail to provide a complete picture on newborn CAH screening:

  • Biochemical Limitations: Biochemical screening has limited sensitivity, with a risk of missing about 20% of simple-virilizing cases. It is also not designed to detect non-classic, mild cases.

  • NGS Limitations: NGS struggles with coverage due to the presence of the highly homologous pseudogene, CYP21A1P-TNXA. The majority of pathogenic variants arise from micro-conversions, large deletions, or chimeric genes derived from this pseudogene, which short-read technology cannot easily resolve.


Targeted LRS Panel for 1ˢᵗ tier Newborn CAH Screening


Berry Genomics has developed a targeted LRS newborn screening panel to address these "dark regions". By utilizing high-throughput LRS platforms (PacBio SMRT technology), we offer a scalable solution that balances cost and clinical utility. This panel can be used to complement existing first-tier screening assays and focuses on common conditions where routine methods struggle with accuracy or turnaround time.


LRS strategy for 21-OHD

Standard Panel

  • 21-Hydroxylase Deficiency (CYP21A2–TNXB): Accurately resolves the gene/pseudogene structure, significantly reducing false positives and unnecessary follow-up while improving sensitivity for mild cases that may require attention.

  • Non-syndromic Hearing Loss (SLC26A4, GJB2, mtRNR1, GJB3): Because physiologic newborn hearing screening has a high false-positive rate and cannot reliably identify moderate-to-mild or late-onset hearing loss, genetic hearing loss screening of the major causative genes (responsible for >40% of severe-to-profound sensorineural hearing loss cases) can enable earlier intervention.

  • Phenylketonuria (PKU) and BH4-deficient HPA (PAH, PTS): Drastically reduces diagnostic turnaround time. While biochemical confirmation requires few steps and can take weeks, genetic testing can provide rapid results to support timely management.

  • G6PD Deficiency (G6PD): Improved sensitivity for detecting female heterozygotes, who are often missed by biochemical screening.


Extension

  • Thalassemia: Provides improved detection of structural variants (SVs), including α-triplications and β-deletions. Those variants are important for identifying some α/β-thalassemia cases early.

  • Spinal Muscular Atrophy: In addition to standard copy-number detection, LRS improves detection of small variants within SMN1.

Ready to Redefine Your Screening?


Whether you are interested in the LRS newborn screening panel or you are looking to design a customized panel tailored to your specific population needs, our team is ready to assist.

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