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. Author manuscript; available in PMC: 2012 Aug 1.
Published in final edited form as: Am J Med Genet A. 2011 Jul 7;155(8):1877–1883. doi: 10.1002/ajmg.a.34087

How High are Carrier Frequencies of Rare Recessive Syndromes? Contemporary Estimates for Fanconi Anemia in the United States and Israel

Philip S Rosenberg 1,2,3, Hannah Tamary 1,2,3, Blanche P Alter 1,2,3
PMCID: PMC3140593  NIHMSID: NIHMS288501  PMID: 21739583

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.

Keywords: Fanconi anemia, gene frequency, prevalence, epidemiologic methods

INTRODUCTION

More than 1100 autosomal recessive syndromes have been characterized and mapped in human populations (http://www.ncbi.nlm.nih.gv/Omim). Often, syndromes are associated with specific populations; the ability to test for founder mutations has enabled screening programs. For example, in Ashkenazi Jews, 16 genetic diseases have a heterozygote frequency of around 1:100 or more, and screening is routinely offered for many of these disorders [Klugman and Gross]. Currently, however, screening is not practical in heterogeneous populations such as the entire United States (US); hence, it is unclear how many persons in the general population carry deleterious mutations of the same genes.

Fanconi anemia (FA) provides an important illustrative example. FA is a mostly autosomal recessive [Auerbach, 2009; de Winter and Joenje, 2009] DNA repair syndrome [D'Andrea, 2010] associated with progressive pancytopenia, acute myeloid leukemia, and specific solid tumors [Alter, 2003; Alter et al., 2003]. Notably high carrier frequencies have been estimated for several founder populations [Callen et al., 2005; Morgan et al., 2005; Rosendorff et al., 1987; Tipping et al., 2001], and FA occurs worldwide [Altay et al., 1997; Bouchlaka et al., 2003; Korgaonkar et al.; Macdougall et al., 1994; Magdalena et al., 2005; Tamary et al., 2000; Tootian et al., 2006; Xie et al., 2001; Yagasaki et al., 2003], but carrier frequencies in different countries remain unknown.

Israel is one country where there are data on national carrier frequencies. Founder mutations have been identified in Jewish populations, e.g. the FANCC IVS+4 A>T mutation in Ashkenazi Jews [Butturini et al., 1994; Whitney et al., 1994] and the FANCA 2172-2173insG mutation in Moroccan Jews [Tamary et al., 2000]. The carrier frequency in Ashkenazi Jews in Israel has been estimated as 1:92 and 1:77 respectively in two large screening studies [Fares et al., 2008; Peleg et al., 2002], comparable to the value of 1:108 in a large study of Ashkenazi Jews in the United States (US) [Strom et al., 2004]. More limited data suggest that carrier frequencies in non-Ashkenazi Israeli Jews may be similar [Tamary et al., 2000]. Founder mutations have also been identified in Israeli Arabs with FA [Tamary et al., 2004], but carrier frequencies have not been surveyed. However, in the nationally inclusive Israeli Fanconi Anemia Registry (ISFAR) [Tamary et al.], 14 of 37 FA (38%) with known mutations were Arabs. Therefore, the overall carrier frequency in Israel in general is likely to be roughly similar to the carrier frequency among Jews, around 1:100 or more common.

In contrast, there are fewer data for the US as a whole. Swift [1971] estimated that the US FA carrier frequency is 1:300 by applying the Hardy-Weinberg law to estimates of the number of FA cases born during a given period with a known overall birth rate [Swift, 1971]. This figure is widely cited. Furthermore, in the literature, a contrast is often drawn between the comparatively high carrier frequency of around 1:100 in certain ethnic groups, including Jews [Carlsson et al., 2004], Afrikaners [Rosendorff et al., 1987] and Spanish Gypsies [Callen et al., 2005], and the comparatively low carrier frequency of around 1:300 reported by Swift. However, this historical estimate was based on surprisingly limited data. To quote the author: “Taking only the families I know, twelve definitive cases have been born in New York State during that period [1956 until 1967] among a total of 4.185×106 live births.” These data are the basis of Swift's calculation that 2[12/4.2 × 106]1/2 ≈ 1:300. However, this result (based on the 12 cases known to the author) is now suspected to be an under-estimate because FA was often under-recognized during that period [Auerbach, 2009; D'Andrea]. Nonetheless, this figure has not been updated even after 40 years.

Given the biological importance of the FA pathway in the etiology of cancer [de Winter and Joenje, 2009] and the current lack of data about carrier frequency heterogeneity in general populations, we sought to update the estimated FA carrier frequency in the US. Therefore, we analyzed a much larger contemporary US dataset from the Fanconi Anemia Research Fund (FARF, 488 persons with FA). We also analyzed Israeli ISFAR data (66 persons with FA) so that results from our approach could be compared with published findings from direct surveys. Our method extends previous work by accounting for systematic uncertainty about the proportion of cases that are ascertained. This is important because failure to account for partial ascertainment necessarily leads to under-estimates.

Using data from these cohorts, we also characterized the survival experience with FA during 1989 – 2010, which could be compared with that for cohort and literature cases. By combining our estimates of incidence and survival, we were able to estimate for the first time the prevalence of persons currently living with FA in the US and Israel. Our approach is developed here for FA, but our methods could be applied to other recessive syndromes.

METHODS

Patients

The Fanconi Anemia Research Fund, Inc (FARF) is the major family and patient support group for FA in North America and perhaps worldwide (http://www.fanconi.org). Records at the FARF include basic demographic data (except ethnicity) on all families and persons with FA who have ever contacted the FARF for information and support. For purposes of this analysis, the FARF provided us with anonymized demographic data on all 488 individuals with FA from the US who ever became known to that organization. These data included date of birth, date of death in persons who have died, and gender. The FARF does not confirm diagnoses, but the diagnosis of FA is highly sensitive and therefore accepted.

The ISFAR is a retrospective cohort of FA patients in Israel who ever received medical care by a hematologist at any of the 16 major pediatric medical centers in Israel [Tamary et al., 2010]. For purposes of this analysis, the ISFAR provided us with the same basic anonymized demographic data as the FARF. We did not request data on ethnicity because the total number of 66 patients precluded reliable analyses for subgroups. Vital status data were considered to be up-to-date as of 1 January 2010 for FARF and 10 February 2008 for ISFAR.

Statistical Analysis

We estimated the probability of surviving up to age a,S(a)in the FARF using both the Kaplan-Meier method and a spline-based smoothing approach, as previously described [Rosenberg, 1995]. We accounted for potential survival bias due to left truncation of follow-up of persons who were born before ascertainment began in earnest by the FARF. We took 1 January 1989 as the approximate start-up time, because 1989 was the year of the FARF's first scientific symposium. Hence, we included follow-up from birth for persons born in 1989 or later; for persons born prior to 1989, we included follow-up beginning at their attained age in 1989 [Klein and Moeschberger, 1997]. We applied the same approach to the ISFAR data. We tested for differences in mortality rates between the two cohorts using the Cox proportional hazards model.

We estimated the carrier frequency as 2q(1 – q)based on the Hardy-Weinberg law [Hartl, 1997]. This approach estimates q as the square root of the FA birth incidence, which is the number of FA births in a given population and time period, IFA, divided by the total number of live births in the same population and time period, ITOT , so that q = (IFA / ITOT)1/2. This estimate of q does not account for differential loss of FA fetuses; therefore, it may be conservative.

For the US, it is clear that recent FA births cannot be fully ascertained by the FARF because a substantial number of younger persons who have FA have not yet been diagnosed (median age of diagnosis in the literature is 7 years [Shimamura and Alter, 2010]). Also, ascertainment of FA births prior to the start-up time is likely to under-estimate the true incidence if families with no surviving affected members as of 1989 are less likely to become known to the FARF. Therefore, we counted FA births during the ascertainment window from 1989 through 2000. We used the same window period for the ISFAR study, reasoning that medical records might be comparatively inaccessible prior to 1989, and recent records cannot include cases who have not yet presented. We took corresponding values of ITOT from census data and assumed these were known without error.

By combining our estimates of FA incidence and survival we estimated P, the number of persons living with FA in the US and Israel. Prevalence estimates were calculated for calendar year 2010 (US) and 2008 (Israel), the respective last follow-up (report) dates for the FARF and ISFAR. To estimate P , we first counted P0, the number of persons with FA who were born before 1989 and who were still alive as of the respective report dates. Then, for each subsequent year, we multiplied the estimated birth incidence per year by the probability of surviving up to the report date, and summed the results. For the US, P=P0+IFA∑t=19892010S(2010−t); for Israel, we used 2008 in place of 2010. Because FA is no longer seen almost exclusively in the pediatric population [Alter et al., 2010], we also estimated the number of adults with FA ages 18 years or older by calculating partial sums through birth years up to 1992 (US) and 1990 (Israel).

Statistical uncertainty in q reflects random variation in IFA ; we calculated a confidence interval for q assuming that annual counts during the window period had a Poisson distribution with a constant rate. We used a bootstrap procedure [Efron and Tibshirani, 1994] to construct a confidence interval for P that incorporated random variation in estimates of both IFA and S(a) . In results CI denotes Confidence Interval.

These procedures account for random variation of q and P, but the estimates must also be adjusted to reflect incomplete ascertainment of FA births during the window period. Because the level of ascertainment is unknown, we considered a broad range of possible values. For example, if the ascertainment was assumed to be 0.5 or 50%, we multiplied the observed birth incidence IFA by 2. Formally, the adjusted estimate of q is [(IFA /ascertainment) /ITOT]1/2. Importantly, when the nominal ascertainment was set to 100% we obtained a conservative lower bound. To reflect both systematic and random variation, we defined a “plausible range” from the lower confidence limit given a high ascertainment value to the upper confidence limit given a low ascertainment value.

RESULTS

Survival experience

In the FARF, 488 persons (265 males, 223 females) contributed 6007 person-years of follow-up between 1989 and January 2010, and there were 185 deaths. In the ISFAR, 66 persons (33 males, 33 females) contributed 1043 persons-years, and there were 21 deaths. The median survival was 24.7 years (95% CI: 21.5 – 27.3 years) in FARF and 28.9 (95% CI: 20.1 – 30.0) years in ISFAR (Fig. 1A). The two curves are not significantly different. The survival curves are consistent with prior reports from cohorts [Alter et al.; Kutler et al., 2003] and literature cases [Alter, 2003; Shimamura and Alter, 2010]. As expected, in the larger US cohort the age-specific mortality rate (Fig. 1B) had a statistically significant peak around age 11, occurring a year or more after the well-characterized peak incidence of severe bone marrow failure [Rosenberg et al., 2003].

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

Figure 1

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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.

Estimates for the US

On average from 1989 through 2000, 15 persons with FA were born each year in the US who eventually became known to the FARF (Fig. 2A), amongst the 4.0 million persons born each year in the US during that period (National Center for Health Statistics, www.dhhs.gov). The corresponding Hardy-Weinberg carrier frequency assuming 100% ascertainment is 1:257 (Fig. 2B); the 95% CI is 1:240 – 1:277. This range describes a lower bound because ascertainment in FARF must be less than 100%. Even so, the lower confidence limit is significantly higher than Swift's estimate [Swift, 1971] of 1:300.

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

Figure 2

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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.).

We considered ascertainment percentages between 40% – 60% to be most plausible, for the following reasons: Given the data, values of 20% or lower appear unlikely because these imply that the carrier frequency is at least 1:100 (Fig. 2B), which is the same range as for small founder populations. Towards the other extreme, values of 80% or higher also seem unlikely because not all persons with FA are recognized. Indeed, one-third of FA patients with cancer had FA diagnosed after cancer [Alter, 2003], and some fraction of those who receive a more timely diagnosis may not be made aware of or be interested in the information available to them through the FARF. Using mid-range ascertainment values of 40% - 60%, we obtain a plausible range for the US carrier frequency of 1:156 – 1:209. The corresponding plausible range for US prevalence (derived using the smoothed survival curve from the FARF) is 550 – 975 persons (Fig. 2C). The plausible range for adults ages 18+ is 190 - 370. For a mid-point estimate assuming 50% ascertainment by FARF, we impute: 31 FA births per year during 1989 – 2000; carrier frequency of 1:181; FA prevalence (all ages combined) of 720; FA prevalence (ages 18+) of 260.

Estimates for Israel

In the ISFAR 2.6 FA births per year were observed during the period 1989 – 2000 (Fig. 2D). We assumed 50% – 100% ascertainment by ISFAR since cases were identified through a countrywide hospital network. We also used the US survival experience to estimate the Israeli prevalence because the US curve was more reliable (Fig. 1). For the entire country of Israel (Jews and non-Jews combined), we obtained a plausible range for the carrier frequency of 1:66 – 1:128 (Fig. 2E). This range is broadly consistent with direct surveys. The corresponding plausible range for Israeli prevalence is 40 – 135 persons (Fig. 2F). The plausible range for adults ages 18+ is 10 – 40. For a mid-point estimate assuming 75% ascertainment by ISFAR, we impute: 3.4 FA births per year during 1989 - 2000; carrier frequency of 1:93; FA prevalence (all ages combined) of 70; FA prevalence (ages 18+) of 20. Results were very similar using the Israeli survival curve (data not shown).

DISCUSSION

Our analysis suggests that the FA carrier frequency in the US may be higher than previously thought, around 1:181. Our lower plausible limit of 1:209 is about 30% higher than Swift's prior estimate of 1:300. This value assumes that the FARF has ascertained 60% of all cases; the estimate decreases to 1:257 - but still remains higher than Swift's – in the very implausible scenario where the FARF has achieved 100% ascertainment. From the perspective of population genetics, our contemporary estimate narrows the gap between the average carrier frequency in the US and higher carrier frequencies of around 1:100 reported for a number of ethnic groups including Ashkenazi Jews. This is consistent with the facts that the general US population is a heterogeneous mixture of descendents of many ancestral groups with many genotypes, and FA is found worldwide. However, the ethnic groups with well-characterized founder mutations [Bouchlaka et al., 2003; Callen et al., 2005; Magdalena et al., 2005; Morgan et al., 2005; Tamary et al., 2000; Yagasaki et al., 2003] represent a small proportion of the general US population.

The indirect method (estimating the carrier frequency 2q(1 – q)from the number of affected births assuming the Hardy-Weinberg law) is most useful when direct surveys are not feasible. This approach is applicable to any recessive syndrome that affects multiple founder populations. All that is required is consistent ascertainment of affected individuals in the entire population of interest and prospective follow-up on vital status. As shown here, this is achievable through established family support groups (i.e. the FARF) or nationally representative case series (i.e. the ISFAR).

The indirect method usually provides a useful estimate even when there is population substructure that tends to make the estimate too large [Hartl, 1997]. In contrast, in the presence of genetic heterogeneity the estimate will tend to be too small [Heim et al., 1992]. Both potential biases may have affected our calculations for the US and Israel. Unfortunately, available data do not provide a way to assess the magnitude of these potential biases, nor is not currently feasible to make estimates for subgroups defined by ethnicity or country of origin.

Our application of the Hardy-Weinberg law may also be affected by two conservative biases. First, the formula may under-estimate the true carrier frequency if the spontaneous fetal loss rate is differentially higher in affected fetuses. Second, it may under-estimate the true carrier frequency if a substantial number of affected persons are simply not recognized. For example, it was not known at the time of Swift's report that many persons with FA lack obvious birth abnormalities associated with the syndrome [Shimamura and Alter, 2010]. In South Africa, an early study in Blacks based on hospital-based ascertainment from clinical data alone obtained a very low lower-bound for the birth incidence (1:476,000) and carrier frequency (1:690) [Macdougall et al., 1990]. However, values from a recent screening study in the same population were around 10-fold greater, >1:40,000 and 1:100, respectively [Morgan et al., 2005].

These potential biases may also affect our estimates of prevalence. In addition, even if the estimated birth incidence in the window period is accurate, recent birth incidence may be lower and consequently our prevalence estimates may be biased upwards if more couples are availing themselves of ethnically appropriate screening tests. This is a particular issue regarding our prevalence estimates for Israel, where screening is facilitated by knowledge of founder mutations and readily available prenatal and preimplantation genetic diagnoses. If despite limitations one is willing to provisionally accept our approach, our findings have two additional implications, besides the perspective they provide on the population genetics of FA.

First, the specter of cancer has emerged as a major clinical challenge for persons with FA, but it is unclear how new treatments should be evaluated. Over the lifetime of a person with FA, the cumulative risk of developing a solid tumor is extraordinarily high [Rosenberg et al., 2003]. However, because of the rarity of the syndrome, very few persons with FA will develop one over the calendar time span of a conventional clinical study, say 1 – 3 years. If there are currently ~260 US adults with FA ages 18+, as suggested by this study, given an annual solid tumor incidence of ~1.5%/year [Alter et al., 2010] one would expect just 4 new tumors per year in the whole US FA population. Statistical power constraints strongly suggest that alternatives to traditional randomized therapeutic trials must be considered. For example, it may prove necessary to enroll patients with related syndromes, such as dyskeratosis congenita [Alter et al., 2009], or perhaps, sporadic cases in atypically young patients without obvious risk factors.

Second, it has long been suspected that unaffected carriers of alleles for FA and other recessive DNA repair syndromes may be at significantly increased risk of cancer [Swift, 1976]. This has not been established for FA on the basis of family studies [Berwick et al., 2007; Potter et al., 1983; Swift et al., 1980; Tischkowitz et al., 2008] but those studies may have had limited power. Because FA carrier frequency may be higher than previously thought, this hypothesis should be further explored in the next generation of population-based genetic association studies [Cirulli and Goldstein, 2010; Dickson et al., 2010]. Suitably powered, these studies could definitively determine how many persons in the general population carry known causative alleles for FA and the other recessive cancer syndromes, how many carry other potentially deleterious mutations in the same genes, and whether any of these rare variants play a role in sporadic cancer.

ACKNOWLEDGMENTS

We are grateful to the Fanconi Anemia Research Fund, Inc, for sharing their anonymized data on North American patients with FA. We thank members of the Israeli Society of Pediatric Hematology/Oncology for the Israeli birth rates and FA data.

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