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International approaches to early identification of rare diseases and precision medicine

Pediatric Research (2025)Cite this article

This month’s article, “Unveiling the Hidden Burden: Challenges and Spectrum of Inborn Errors of Metabolism (IEMs) in Low- and Middle-Income Countries (LMICs)”1 demonstrates the global challenge to identify and address rare diseases in pediatrics. Early diagnosis is key to improved child and adult health outcomes, and the advent of next-generation sequencing offers new opportunities. The study reviews IEMs seen in a tertiary care hospital in Pakistan. Many of these conditions manifest early in life with non-specific symptoms and are individually rare, complicating clinical recognition. However, IEMs are highly actionable, and a timely diagnosis is critical to prevent the devastating consequences of a “metabolic crisis”. The authors note the many challenges to identification, testing, and follow-up in providing care for IEMs and discuss barriers, including limited screening, delayed diagnosis, reduced availability of testing, and financial constraints.1 These are real hindrances in all countries, including LMICs and high-income countries. We review the identified barriers and highlight activities in other regions of the world, including Abu Dhabi in the United Arab Emirates, where rates of IEMs are high, and the United States (U.S.). While these countries are very different in socio-demographics, they are moving to whole genome sequencing (WGS) and have addressed the barriers as well as the social and ethical issues in different ways. Both countries offer potential policy approaches for consideration.

In the U.S., universal newborn screening (NBS) for specific, treatable rare conditions has revolutionized early diagnosis, with 98% of infants receiving dried blood spot screening through the state-based public health programs that identify over 7000–12,000 infants annually for timely interventions.2,3 The National Academies of Science, Engineering, and Medicine’s (NASEM) recent report on Newborn Screening in the United States: A Vision for Sustaining and Advancing Excellence3 reviews the U.S. approach and offers many areas in need of improvement. As new screening technologies and disease treatments become available, some programs struggle to keep pace with adding new conditions to screening panels, leading to inconsistent access to testing due to variability in the conditions screened in each of the 50 States. The profound benefits of an expeditious diagnosis for IEMs have prompted “genotype-first” strategies, such as whole genome sequencing (WGS), as an adjunct to biochemical NBS and as an effective test for identifying actionable genomic variation for diseases with later onset.4 DNA sequencing has been used in limited ways in some NBS programs in the U.S. The addition of WGS to the analysis of blood spot samples promises more information and has been shown to be cost-effective, but raises technical, social, ethical, privacy, and implementation questions and adds to the challenge of long-standing financial and workforce constraints.

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References

  1. Mansoor, S. & Khan, Z. Unveiling the hidden burden: challenges and spectrum of inborn errors of metabolism in LMICs. Pediatr. Res. https://doi.org/10.1038/s41390-025-04462-7 (2025).

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Authors and Affiliations

  1. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Tina L. Cheng & Anne Slavotinek

  2. Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Tina L. Cheng & Anne Slavotinek

  3. Director of Research, Consultant Rheumatology, SEHA, Abu Dhabi, United Arab Emirates

    Amna Ahmed Al Muhairi

  4. Executive Director Research, PureHealth, Dubai, United Arab Emirates

    Bindhya Cariappa

  5. University of Colorado, Colorado Children’s, Boulder, USA

    David Keller

  6. Academic Pediatric Association, McLean, VA, USA

    Mona Patel & Maya Ragavan

  7. American Pediatric Society, The Woodland, TX, USA

    Scott Lorch & Lisa Chamberlain

  8. Association of Medical School Pediatric Department Chairs, McLean, VA, USA

    Tina Cheng & Joseph St. Geme

  9. Society for Pediatric Research, The Woodland, TX, USA

    Ashwini Lakshmanan & Tom Mariani

Authors
  1. Tina L. Cheng
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  2. Amna Ahmed Al Muhairi
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  3. Anne Slavotinek
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  4. Bindhya Cariappa
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On behalf of the Pediatric Policy Council

  • David Keller
  • , Mona Patel
  • , Maya Ragavan
  • , Scott Lorch
  • , Lisa Chamberlain
  • , Tina Cheng
  • , Joseph St. Geme
  • , Ashwini Lakshmanan
  •  & Tom Mariani

Corresponding author

Correspondence to Tina L. Cheng.

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Competing interests

Cheng is the consulting editor of Pediatric Clinics of North America. No other conflicts to disclose from all authors.

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Cheng, T.L., Al Muhairi, A.A., Slavotinek, A. et al. International approaches to early identification of rare diseases and precision medicine. Pediatr Res (2025). https://doi.org/10.1038/s41390-025-04695-6

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