Malattia di Fabry: un rischio per la salute nascosto

Titolo: Estimating the prevalence of late-onset Fabry disease in the US in 2024

Estratto: Fabry disease is a rare lysosomal storage condition in which sphingolipid levels build up to harmful levels in various bodily organs, eventually leading to life-threatening complications such as stroke and kidney failure. Fabry disease is caused by rare pathogenic alleles in the GLA gene on chromosome X and may present as an early or late-onset disease depending on the identity of the causal allele and the severity of its effect on the gene product. Epidemiological studies have widely varied in their estimation of Fabry disease prevalence: estimates based on reported clinical cases range from 1 in 40,000 to 1 in 170,000 individuals, whilst recent estimates based on newborn screening are much higher, ranging from 1 in 1,250 to 1 in 21,973 individuals. The primary aim of this study was to estimate the prevalence of Fabry disease in the US in 2024 by analysing selected GLA variants mostly associated with late-onset Fabry disease, projecting their allele frequencies to the US population and applying penetrance data from the literature to calculate how many causal allele carriers would be expected to be symptomatic for the disease at some point within their lifetime. 8 causal genetic variants were selected for analysis in this study based on their inclusion in a previous Fabry disease study using data from the UK Biobank. Allele frequencies for all 8 variants in global ancestry groups were extracted from gnomAD v4.1. The size and demographic makeup of the US population in 2024 was obtained from the US Census Bureau and mapped to gnomAD v4.1 ancestry groups, using previously reported estimates of the ancestral composition of Census groups encompassing multiple ancestry groups. Carrier counts by sex and ethnic group were calculated by projecting the summed allele frequencies to the US population using the Hardy-Weinberg equation and taking into consideration the X-linked mode of inheritance, assuming each individual can only carry 1 pathogenic variant. It was found that pathogenic alleles are present in the gnomAD v4.1 sample for all variants in the non-Finnish European gnomAD ancestry group, for 2 variants in South Asian ancestry group, and for 1 variant in the African / African American and East Asian ancestry groups. For the remaining 5 ancestry groups, there are no pathogenic alleles recorded in the gnomAD v4.1 dataset across all 8 variants included for analysis in the study. Results show the highest pathogenic allele carrier frequencies in the European (non-Finnish) ancestry group, followed by the South Asian, East Asian and African / African American ancestry groups. Using reported penetrance figures of 100% for males and 70% for females, it is estimated that the carrier and symptomatic populations of Fabry disease in the US in 2024, based on analysis of the 8 included variants, are 12,024 male carriers (or 1 in 14,022 males) who will all develop symptoms, and 24,845 female carriers (or 1 in 6,978 females), of whom 17,392 will develop symptoms. Of these carriers who will develop symptoms, around 98.6% (corresponding to 11,858 men and 17,153 women) will carry a variant primarily associated with late-onset or both forms of Fabry disease. The prevalence figures presented in this study are significantly higher than those based on reported clinical cases and are in line with those presented more recently based on newborn screening studies and with the prevalence reported in the UK Biobank analysis. The US National Institute of Health reports Fabry disease prevalence at around 1 in 50,000 males (which would correspond to 1 in 25,000 females). Analysing just 8 of the potentially hundreds of causal variants within the GLA gene, this study suggests that Fabry disease may be over 3 times as prevalent as is currently believed. This work highlights the vast potential of large genetic databases to analyse rare diseases, which will continue to progress as these datasets add more data, which will improve their power and diversity. What Is Already Known On This TopicO_LIFabry Disease is a rare X-linked lysosomal storage disorder with historical prevalence estimates ranging from 1 in 40,000 to 1 in 170,000 males, based on case ascertainment. C_LIO_LIMore recent newborn screening studies that test alpha-galactosidase A activity or perform genetic testing within the GLA gene, in addition to a UK Biobank study examining the prevalence of selected causal Fabry disease variants, have consistently suggested that Fabry disease may be far more prevalent than the estimates based on case ascertainment. C_LI What This Study AddsO_LITo our knowledge, this is the first study providing population-level estimates of the number of causal Fabry disease carriers and of the symptomatic population in the US using publicly available data from gnomAD v4.1. Our estimates are consistent with those produced by newborn screening studies and the UK Biobank analysis, and suggest that late-onset Fabry disease may affect >1 in 10,000 people in the US in 2024 at some point during their lifetime. C_LIO_LIThis study also demonstrates the potential of large genetic databases, such as gnomAD, for the study of rare genetic diseases, which are often misdiagnosed and may consequently be believed to be rarer than they are in reality. C_LI How This Study May Affect ResearchO_LIThis study highlights two areas for improvement which would be significantly beneficial to the study of rare genetic diseases. {circ}While this study demonstrates the utility of genetic databases to study certain rare genetic diseases, it is likely that the study of rarer conditions, in particular those manifesting during childhood and/or with a dominant mode of inheritance, would be more difficult using genetic databases, as individuals with such conditions are less likely to be included in population-level genetic biobanks (such as UK Biobank) due to a healthy volunteer bias. It is important that future genetic datasets are more representative in their recruitment to ensure that rare genetic diseases are not systematically excluded or underrepresented among participants. Studies such as All Of Us in the US, and Our Future Health and the Generation Study in the UK, will be extremely helpful in addressing this point. {circ}Estimates of the symptomatic Fabry disease population in the US in 2024 were calculated using the most up-to-date penetrance estimates in males and females. However these estimates were calculated using individuals already present in a Fabry registry and therefore may overestimate the penetrance, and especially among females, since asymptomatic carriers may be less likely to join a disease registry. Accurate calculation of the symptomatic population with a given genetic disease relies upon accurate penetrance estimates, which are not always available. These estimates are best calculated from large population-level resources with linked genetic and electronic health record data. C_LI