Classical homocystinuria: A common inborn error of metabolism? An epidemiological study based on genetic databases.

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 similar to 0.38:100,000, and the incidence was higher in Europeans non-Finnish (similar to 0.72:100,000) and Latin Americans (similar to 0.45:100,000) and lower in Africans (similar to 0.20:100,000) and Asians (similar to 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.