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Classical homocystinuria: A common inborn error of metabolism? An epidemiological study based on genetic databases
Giovana R Weber Hoss1,2,3, Fernanda Sperb-Ludwig1,2, Ida V D Schwartz1,2,3
1BRAIN Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Insights
Classical homocystinuria (HCU), caused by CBS gene variants, has a minimal worldwide incidence of approximately 0.38 per 100,000 births. Incidence varies by ethnicity, being higher in Europeans and lower in Asians.
Area of Science:
- Genetics
- Metabolic Disorders
- Population Health
Background:
- Classical homocystinuria (HCU) is primarily caused by biallelic pathogenic variants in the CBS gene.
- Previous HCU prevalence estimates vary, with figures from clinical records around 0.82:100,000 and neonatal screening suggesting 1.09:100,000.
Purpose of the Study:
- To determine the minimal worldwide incidence of classical homocystinuria (HCU).
Main Methods:
- Identified the 25 most frequent pathogenic alleles for HCU via literature review.
- Estimated HCU incidence using the allele frequency in the gnomAD genomic database.
Main Results:
- The minimal worldwide incidence of HCU was estimated at approximately 0.38 per 100,000 births.
- Incidence rates varied significantly by population: higher in non-Finnish Europeans (~0.72:100,000) and Latin Americans (~0.45:100,000), and lower in Africans (~0.20:100,000) and Asians (~0.02:100,000).
Conclusions:
- The study's findings align with existing meta-analyses on HCU incidence.
- The estimated incidence in Europeans was lower than in small Northern European studies but consistent with neonatal screening data.
- The large dataset and population coverage provided a more precise HCU incidence estimation.
Background:
Biallelic pathogenic variants in CBS gene cause the most common form of homocystinuria, the classical homocystinuria (HCU). The worldwide prevalence of HCU is estimated to be 0.82:100,000 [95% CI, 0.39-1.73:100,000] according to clinical records and 1.09:100,000 [95% CI, 0.34-3.55:100,000] by neonatal screening. In this study, we aimed to estimate the minimal worldwide incidence of HCU.
Methods:
The 25 most common pathogenic alleles of HCU were identified through a literature review. The incidence of HCU was estimated based on the frequency of these common pathogenic alleles in a large genomic database (gnomAD).
Results:
The minimum worldwide incidence of HCU was estimated to be ~0.38:100,000, and the incidence was higher in Europeans non-Finnish (~0.72:100,000) and Latin Americans (~0.45:100,000) and lower in Africans (~0.20:100,000) and Asians (~0.02:100,000).
Conclusion:
Our data are in accordance with the only published metanalysis on this topic. To our surprise, the observed incidence of HCU in Europeans was much lower than those described in articles exploring small populations from northern Europe but was similar to the incidence described on the basis of neonatal screening programs. In our opinion, this large dataset analyzed and its population coverage gave us greater precision in the estimation of incidence.
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