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Biological factor, barrier 4 of 6

Genetic disorders

Inherited disorders such as sickle cell disease cause many child deaths and learning difficulties, but much of the harm depends on whether screening and treatment are available. Newborn screening and early treatment for phenylketonuria show the barrier can be removed (U.S. Preventive Services Task Force, 2008).

Evidence

  • Sickle cell disease worldwide. In 2021 an estimated 7.74 million people were living with it and 515,000 babies were born with it, mostly in the Caribbean and in western and central sub-Saharan Africa. Deaths it contributed to totaled about 376,000, including 81,100 children under 5 (GBD 2021 Sickle Cell Disease Collaborators, 2023). Data on child mortality in Africa are inadequate for definitive statements (Grosse et al., 2011).
  • School performance. In a U.S. sample, students with sickle cell disease scored 0.70, 0.87, and 0.80 standard deviations below norms in reading, math, and spelling. Environmental factors such as socioeconomic status are also associated with cognitive outcomes in this group (Heitzer et al., 2021, Prussien et al., 2020).
  • Phenylketonuria. Newborn screening and early dietary treatment substantially improve brain development and prevent the severe intellectual disability the disorder otherwise causes. Treated children often still score below the IQ predicted from their parents and siblings (U.S. Preventive Services Task Force, 2008).
  • Link to malaria. The gene became common in tropical regions because carriers are more likely to survive malaria (Uyoga et al., 2019).

What can be done

Actions rated on the strength-rating scale (A strong and replicated, B solid but limited, C weak or debated, D contested or failed), applied to the specific claim made.

  • Hydroxyurea for children with sickle cell anemia in Africa (B, C for the mortality figure). In a placebo-controlled trial in Uganda, sickle cell events were 45% versus 69% and malaria did not increase (Opoka et al., 2017), and raising the dose toward the maximum tolerated level worked better than a fixed dose (John et al., 2020). In the REACH study of 606 children, death rates fell from 3.6 to 1.1 per 100 patient-years, but this compared the same children before and during treatment without a control group (Tshilolo et al., 2019). A conference survey of health professionals reported a median price of about $19 a month for a 30 kg child (C) (Keza et al., 2023).
  • Folic acid fortification of flour (B). A 2026 meta-analysis of before-and-after studies found 44% fewer neural tube defects (Moges, Kotiso, and Jaldo, 2026). Seventy countries require it, and an estimated 200,000 preventable cases a year still occur in countries without it (Kancherla et al., 2026).
  • Sickle cell screening linked to care (B). Screening newborns and giving penicillin is estimated to be highly cost-effective in 24 of 47 sub-Saharan countries, at about $184 per healthy life-year gained (Kuznik et al., 2016). Penicillin cut serious pneumococcal infections by 84% in the original trial (Gaston et al., 1986), though Cochrane rates the evidence low certainty (Rankine-Mullings and Owusu-Ofori, 2021). Point-of-care tests costing a few dollars were highly accurate (Christopher et al., 2022), and in Angola 92% of children identified with them were linked to care, versus 56% in an earlier pilot that used laboratory testing (Olaniyan et al., 2023). Uganda began mandatory national screening in February 2026 (Jonani et al., 2026).
  • Ultrasound screening for stroke risk with transfusion (B). Regular transfusion cut stroke risk by 92% in children with abnormal scans (Adams et al., 1998). Where transfusion is not feasible, a Nigerian trial comparing two hydroxyurea doses could not show a difference in strokes (Abdullahi et al., 2022).
  • Voluntary carrier screening for thalassemia (B). Iran's national program, which combines premarital screening, counseling, and prenatal diagnosis, saw about 81% fewer affected births than expected (Hadipour Dehshal et al., 2014). Such programs raise ethical concerns, including coercion when linked to marriage, stigma for carriers, and decisions about ending a pregnancy, so best practice is voluntary, confidential testing with neutral counseling.
  • Newborn screening for congenital hypothyroidism (B for the coverage figure). Screening has largely prevented the intellectual disability this condition causes where it exists, but about 70% of newborns worldwide still lacked access in 2025 (Arrigoni et al., 2025), almost unchanged from about 71% in 2014 (Ford and LaFranchi, 2014).
  • Not yet scalable: gene therapies (B for the facts, limited population impact). Two therapies approved in December 2023 freed most patients in small trials from severe pain crises (FDA, 2023), but their list prices are $2.2 million and $3.1 million per patient (BioPharma Dive, 2023).

Proposed and experimental methods

Methods that are proposed, under trial, approved in some places, or tried and then failed. Each shows a stage label and an evidence rating. A stage label shows how far a method has progressed, not whether it works. The stage labels are explained on the biological factor page.

  • CRISPR gene therapy for sickle cell disease with outcomes-based payment (Approved but not scaled, B). Builds on the gene therapy entry above. In the single-arm exa-cel (Casgevy) trial, 29 of 30 evaluable patients (97%) had no severe pain crises for at least 12 months, after chemotherapy to clear the bone marrow (Frangoul et al., 2024). Under a CMS model, the federal government negotiates discounts for state Medicaid programs, with rebates if the therapy does not deliver its promised benefit, and manufacturers pay for fertility preservation. In July 2025, 33 states plus DC and Puerto Rico had signed on, covering 84% of Medicaid beneficiaries with sickle cell disease (CMS, 2025), and the model page now lists 32 states plus DC and Puerto Rico, with Vertex and Genetix Biotherapeutics as the manufacturers (CMS, 2026). No data on uptake or patient outcomes under the model have been published.
  • Newborn genome sequencing (Large trial, B). In the first BabySeq study of 159 newborns, sequencing found a risk of childhood-onset disease in 9.4%, none predicted by family history, and carrier status in 88% (Ceyhan-Birsoy et al., 2019). In New York's GUARDIAN study, 72.0% of approached families consented, and 3.7% of the first 4,000 newborns screened positive, including treatable conditions not on standard screening panels, but the authors note that further studies must show whether sequencing changes care and improves health (Ziegler et al., 2025). England's Generation Study began in October 2024 and aims to sequence up to 100,000 newborns for over 200 conditions (Genomics England, 2024).
  • Personalized in vivo base editing (Early trial, C). An infant with severe CPS1 deficiency, a urea cycle disorder with about 50% mortality in early infancy, received a custom base editor delivered in lipid nanoparticles at about 7 and 8 months of age, and in the 7 weeks after the first infusion could eat more protein and take half the starting dose of a nitrogen-scavenger drug, with no serious adverse events (Musunuru et al., 2025). FDA leaders then set out a new "plausible mechanism" pathway for approving such individualized therapies (Prasad and Makary, 2025). It is one patient with short follow-up.
  • In utero enzyme replacement therapy (Early trial, C). A fetus with a severe form of infantile-onset Pompe disease (CRIM-negative), whose two affected siblings had died, received enzyme replacement before birth, and at 13 months had normal heart function, age-appropriate motor function, and normal biomarker levels (Cohen et al., 2022). This is a single case.
  • Polygenic embryo screening (Sold commercially without trials, contested, D). Companies sell selection of IVF embryos by polygenic scores, which add up many small genetic effects (Turley et al., 2021). Modelling with real genomes estimated an average gain of about 2.5 cm in height or 2.5 IQ points from choosing the top-scoring embryo, with wide prediction intervals (Karavani et al., 2019). A review by geneticists found many factors lower the predictive power of these scores for embryo selection and warned of selecting for adverse traits and worsening inequality (Turley et al., 2021).

Sources cited on this page

  1. GBD 2021 Sickle Cell Disease Collaborators (2023). Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the Global Burden of Disease Study 2021. Lancet Haematology, 10(8), e585-e599. DOI00118-7) B Moderate
  2. Uyoga, S., Macharia, A. W., Mochamah, G., et al. (2019). The epidemiology of sickle cell disease in children recruited in infancy in Kilifi, Kenya: a prospective cohort study. Lancet Global Health, 7(10), e1458-e1466. DOI30328-6) A Strong
  3. Grosse, S. D., Odame, I., Atrash, H. K., Amendah, D. D., Piel, F. B., & Williams, T. N. (2011). Sickle cell disease in Africa: a neglected cause of early childhood mortality. American Journal of Preventive Medicine, 41(6 Suppl 4), S398-S405. DOI C Limited
  4. Heitzer, A. M., Hamilton, L., Stafford, C., Gossett, J., Ouellette, L., Trpchevska, A., King, A. A., Kang, G., & Hankins, J. S. (2021). Academic performance of children with sickle cell disease in the United States: a meta-analysis. Frontiers in Neurology, 12, 786065. DOI B Moderate
  5. Prussien, K. V., et al. (2020). Correlates of cognitive function in sickle cell disease: a meta-analysis. Journal of Pediatric Psychology, 45(2), 145-155. DOI B Moderate: for the association, C for any causal reading
  6. U.S. Preventive Services Task Force (2008). Screening for phenylketonuria: reaffirmation recommendation statement (American Family Physician) A Strong
  7. Abdullahi, S. U., Jibir, B. W., Bello-Manga, H., Gambo, S., Inuwa, H., Tijjani, A. G., et al. (2022). Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): A double-blind, multicentre, randomised, phase 3 trial. The Lancet Haematology, 9(1), e26-e37. link B Moderate
  8. Adams, R. J., McKie, V. C., Hsu, L., Files, B., Vichinsky, E., Pegelow, C., et al. (1998). Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. New England Journal of Medicine, 339(1), 5-11. link B Moderate
  9. Arrigoni, M., Zwaveling-Soonawala, N., LaFranchi, S. H., van Trotsenburg, A. S. P., & Mooij, C. F. (2025). Newborn screening for congenital hypothyroidism: Worldwide coverage 50 years after its start. European Thyroid Journal, 14(1), e240327. link B Moderate
  10. Christopher, H., Josephat, E., Kaywanga, F., Saul, S., Mshana, I., Kunambi, P., et al. (2022). Potential of point of care tests for newborn screening for sickle cell disease: Evaluation of HemotypeSC™ and sickle SCAN® in Tanzania. International Journal of Laboratory Hematology, 44(5), 959-965. link B Moderate
  11. Ford, G., & LaFranchi, S. H. (2014). Screening for congenital hypothyroidism: A worldwide view of strategies. Best Practice & Research Clinical Endocrinology & Metabolism, 28(2), 175-187. link B Moderate: (raised from C on October 7, 2026, because the 2025 update confirms the estimate)
  12. Gaston, M. H., Verter, J. I., Woods, G., Pegelow, C., Kelleher, J., Presbury, G., et al. (1986). Prophylaxis with oral penicillin in children with sickle cell anemia: A randomized trial. New England Journal of Medicine, 314(25), 1593-1599. link B Moderate
  13. Hadipour Dehshal, M., Tabrizi Namini, M., Ahmadvand, A., Manshadi, M., Sadeghian Varnosfaderani, F., & Abolghasemi, H. (2014). Evaluation of the national prevention program in Iran, 2007-2009: The accomplishments and challenges with reflections on the path ahead. Hemoglobin, 38(3), 179-187. link B Moderate
  14. John, C. C., Opoka, R. O., Latham, T. S., Hume, H. A., Nabaggala, C., Kasirye, P., et al. (2020). Hydroxyurea dose escalation for sickle cell anemia in sub-Saharan Africa. New England Journal of Medicine, 382(26), 2524-2533. link B Moderate
  15. Jonani, B., Nakawuka, B., Ssebunya, E., Kwizera, R., Bongomin, F., & Mboowa, G. (2026). Uganda's mandatory newborn sickle cell disease screening programme: Translating a decade of evidence into differentiated implementation. Pediatric Health, Medicine and Therapeutics, 17, 621156. link (article number as listed in PubMed, unconfirmed against publisher) B Moderate: for the launch fact, C for the cost figure
  16. Kancherla, V., Wagh, K., & Pachón, H. (2026). A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2024. Birth Defects Research, 118(5), e70065. link B Moderate
  17. Keza, G. K., Diallo, D. A., Diagne, I., de Montalembert, M., Corbasson, A., Bernaudin, F., et al. (2023). Availability and cost of basic drugs for sickle cell disease in 13 African countries [Conference abstract]. Blood, 142(Suppl. 1). American Society of Hematology 65th Annual Meeting. link C Limited
  18. Kuznik, A., Habib, A. G., Munube, D., & Lamorde, M. (2016). Newborn screening and prophylactic interventions for sickle cell disease in 47 countries in sub-Saharan Africa: A cost-effectiveness analysis. BMC Health Services Research, 16, 304. link B Moderate
  19. Moges, S., Kotiso, K. S., & Jaldo, M. M. (2026). The effectiveness of mandatory folic acid fortification compared with pre-fortification periods on reducing neural tube defects (NTDs): A systematic review and meta-analysis. BMC Nutrition, 12(1), 31. link (published 13 January 2026, PMID 41526993) B Moderate
  20. Olaniyan, H. S., Briscoe, C., Muhongo, M., Pascoal, R., Armando, A., Santos, B., & McGann, P. T. (2023). Early diagnosis of sickle cell disease at birth hospitals and vaccination centers in Angola using point-of-care tests. Blood Advances, 7(19), 5860-5867. link B Moderate
  21. Opoka, R. O., Ndugwa, C. M., Latham, T. S., Lane, A., Hume, H. A., Kasirye, P., et al. (2017). Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): A trial for children with sickle cell anemia. Blood, 130(24), 2585-2593. link B Moderate
  22. Rankine-Mullings, A. E., & Owusu-Ofori, S. (2021). Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database of Systematic Reviews, 2021(3), CD003427. link B Moderate
  23. Tshilolo, L., Tomlinson, G., Williams, T. N., Santos, B., Olupot-Olupot, P., Lane, A., et al. (2019). Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa. New England Journal of Medicine, 380(2), 121-131. link C Limited: for mortality, B for feasibility and safety
  24. Ceyhan-Birsoy, O., Murry, J. B., Machini, K., Lebo, M. S., Yu, T. W., Fayer, S., et al. (2019). Interpretation of genomic sequencing results in healthy and ill newborns: Results from the BabySeq Project. American Journal of Human Genetics, 104(1), 76-93. link B Moderate
  25. Cohen, J. L., Chakraborty, P., Fung-Kee-Fung, K., Schwab, M. E., Bali, D., Young, S. P., et al. (2022). In utero enzyme-replacement therapy for infantile-onset Pompe's disease. New England Journal of Medicine, 387(23), 2150-2158. link C Limited
  26. Frangoul, H., Locatelli, F., Sharma, A., Bhatia, M., Mapara, M., Molinari, L., et al. (2024). Exagamglogene autotemcel for severe sickle cell disease. New England Journal of Medicine, 390(18), 1649-1662. link B Moderate
  27. Karavani, E., Zuk, O., Zeevi, D., Barzilai, N., Stefanis, N. C., Hatzimanolis, A., et al. (2019). Screening human embryos for polygenic traits has limited utility. Cell, 179(6), 1424-1435.e8. link B Moderate
  28. Musunuru, K., Grandinette, S. A., Wang, X., Hudson, T. R., Briseno, K., Berry, A. M., et al. (2025). Patient-specific in vivo gene editing to treat a rare genetic disease. New England Journal of Medicine, 392(22), 2235-2243. link C Limited
  29. Prasad, V., & Makary, M. A. (2025). FDA's new plausible mechanism pathway. New England Journal of Medicine, 393(23), 2365-2367. link B Moderate
  30. Turley, P., Meyer, M. N., Wang, N., Cesarini, D., Hammonds, E., Martin, A. R., et al. (2021). Problems with using polygenic scores to select embryos. New England Journal of Medicine, 385(1), 78-86. link B Moderate
  31. Ziegler, A., Koval-Burt, C., Kay, D. M., Suchy, S. F., Begtrup, A., Langley, K. G., et al. (2025). Expanded newborn screening using genome sequencing for early actionable conditions. JAMA, 333(3), 232-240. link B Moderate

Every source for this factor is listed on the biological factor page.