How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel

Abstract

For many recessive genetic syndromes, carrier frequencies have been assessed through screening studies in founder populations but remain unclear in heterogeneous populations. One such syndrome is Fanconi Anemia (FA). FA is a model disease in cancer research, yet there are no contemporary data on carrier frequency or prevalence in the general United States (US) population or elsewhere. We inferred carrier frequency from birth incidence using the Hardy-Weinberg law. We estimated prevalence using birth incidence and survival data. We defined "plausible ranges" to incorporate uncertainty about completeness of case ascertainment. We made estimates for the US and Israel using demographic data from the Fanconi Anemia Research Fund and Israeli Fanconi Anemia Registry. In the US, a plausible range for the carrier frequency is 1:156-1:209 [midpoint 1:181]; we estimate that 550-975 persons were living with FA in 2010. For Israel, a plausible range for the carrier frequency is 1:66-1:128 [midpoint 1:93] in line with founder screening studies; we estimate that 40-135 Israelis were living with FA in 2008. The estimated US FA carrier frequency of 1:181 is significantly higher than the historical estimate of 1:300; hence, the gap may be narrower than previously recognized between the US carrier frequency and higher carrier frequencies of around 1:100 in several founder groups including Ashkenazi Jews. Assessment of cancer risks in heterozygous carriers merits further study. Clinical trials in FA will require co-ordination and innovative design because the number of living US patients is probably less than 1,000.

Figure 1. Survival experience of persons with FA in the US (FARF) and Israeli (ISFAR) cohorts

A. Proportion alive by age: black curves, US; grey curves, Israel. For each country, solid lines show spline-smoothed survival curves, shaded regions show corresponding point-wise 95% bootstrap confidence limits, and dash curves show Kaplan-Meier estimates. B. Spline-smoothed age-specific mortality rates (all-cause mortality rate per year among persons with FA surviving to a given age), with point-wise 95% confidence limits, in the US and Israeli cohorts.

Figure 2. Carrier frequency and prevalence of FA in the US and Israel

A. Number of FA births per year in the US eventually known to the FARF. Superimposed is the average number of FA births during the 1989 – 2000 window period, with 95% confidence limits (shaded area). B. Carrier frequency in the US based on the Hardy-Weinberg law (y-axis), conditional on different assumed values for ascertainment of FA births by the FARF (x-axis). C. Number of persons living with FA in 2010 in the US, based on a statistical model combining carrier frequencies in panel B with survival experience in Figure 1. Bars show 95% confidence limits. D.-F. Corresponding estimates for Israel: FA births known to ISFAR (D.); carrier frequencies assuming ascertainment from 50% - 100% (E.); FA Prevalence in Israel in 2008 (F.).