November 2018
Volume 59, Issue 13
Open Access
Letters to the Editor  |   November 2018
Penetrance of the ABCA4 p.Asn1868Ile Allele in Stargardt Disease
Author Affiliations & Notes
  • Rando Allikmets
    Departments of Ophthalmology, Columbia University, New York, New York, United States
    Pathology & Cell Biology, Columbia University, New York, New York, United States.
  • Jana Zernant
    Departments of Ophthalmology, Columbia University, New York, New York, United States
  • Winston Lee
    Departments of Ophthalmology, Columbia University, New York, New York, United States
Investigative Ophthalmology & Visual Science November 2018, Vol.59, 5564-5565. doi:
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      Rando Allikmets, Jana Zernant, Winston Lee; Penetrance of the ABCA4 p.Asn1868Ile Allele in Stargardt Disease. Invest. Ophthalmol. Vis. Sci. 2018;59(13):5564-5565.

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      © ARVO (1962-2015); The Authors (2016-present)

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We read with interest the manuscript by Runhart et al.,1 which further confirmed our recent discovery of the c.5603A>T (p.Asn1868Ile) variant in the ABCA4 gene as the causal mutation in Stargardt (STGD1) and related diseases.2 We had demonstrated that the variant, which is highly frequent in all populations, especially in the general population of non-Finnish Europeans (minor allele frequency [MAF] ∼7%) and therefore considered benign, is actually causal when in trans with a loss-of-function allele.2 It is reassuring that Runhart and colleagues validated all conclusions of our study, that the variant is frequent in STGD1, segregates with the disease phenotype, and results in a predominantly late-onset disease phenotype that at times can be misdiagnosed as age-related macular degeneration (AMD). The only new conclusion, which came to our attention, is that the penetrance of the p.Asn1868Ile allele, when in trans with a “severe” ABCA4 mutation, is estimated at less than 5%. This conclusion was based on calculations of allele frequencies from the gnomAD database and the observation of two sibling pairs where the genotype did not properly segregate with the disease. 
We find this conclusion of extremely low penetrance of the variant incompatible with the authors' own data showing its segregation with the disease in families, which the authors correctly use to support pathogenicity. As a basic principle of genetics, no segregation would be observed even at 50% penetrance (10 times higher than proposed) in the case of a recessive disease. The phenotypic variability associated with this variant adds further uncertainty to the assessment of “non-segregation” as the authors concede that even those individuals with no clinical signs of STGD1 can develop the disease at a later time since they do document disease onset in some cases at a very advanced age, over 70 years.1 Therefore, it is unclear how the study corroborates the conclusion of <5% penetrance with their own data. The authors may also want to re-examine the penetrance calculations with respect to the following considerations: 
First, using MAFs from the general population data in gnomAD, instead of those specific to their Dutch patient population, is incorrect. Significant differences in ABCA4 allele frequencies have been described not only between racial groups3,4 but also between ethnicities/nationalities.5,6 It is clear from the manuscript that many frequent deleterious mutations are very rare or absent in the Dutch population and even the frequency of the p.Asn1868Ile has not been established in The Netherlands. 
Second, the prevalence of ABCA4 disease is not known. The 1:10,000 estimate comes from the textbook chapter by Blacharski in 1988,7 which is frequently cited but likely not read, since it states “We have seen this condition much more commonly than retinoblastoma, which has been estimated at 1 in 15,000 live births. Fundus flavimaculatus is not as common as retinitis pigmentosa, which has a prevalence of no more than 1 in 5000. We have roughly estimated the incidence to be between 1 in 8000 and 1 in 10,000.” We suggest that this is not an appropriate way to determine a disease prevalence, especially as a variable for statistical calculations. The actual prevalence of ABCA4 disease is very difficult to estimate due to enormous clinical heterogeneity, variable age of onset, and (still) incomplete genetic data. 
Third, we stated2 that the p.Asn1868Ile is penetrant in cases where the other allele is “deleterious” or “loss-of-function,”2,8 not “severe.”1 Differentiating between these two categories is very difficult, but it is clear that the functional outcome of an allele cannot be determined by its appearance; that is, even many nonsense mutations may not result in a complete loss-of-function while certain missense alleles do.9,10 In fact, we suggested, based on the empirical data, that cases with p.Asn1868Ile are a “litmus test” for severity of the allele in trans, including all classes of mutations.2 
Fourth, the authors suggest that both genetic and environmental modifiers are the cause of the very low penetrance. Modifiers certainly play a role in expression of ABCA4 disease, but these have to be specifically identified to make such a statement. For example, although the c.2588G>C ([p.Gly863Ala, Gly863del]) variant had been previously considered a “mutation,”11 we presented new data showing that it is in fact a modifier for the p.Asn1868Ile variant. It does not cause the disease alone, but the complex allele, together with the p.Asn1868Ile mutation, becomes a fully penetrant, disease-causing mutation.2 
In summary, there is a glaring inconsistency between the almost perfect segregation data and the authors' conclusion of very low penetrance of the p.Asn1868Ile variant. The latter stems from using questionable assumptions in their estimation of the disease prevalence, MAF of variants in their population, and the functional consequence of the variants. The published data1,2 suggest the exact opposite, at least 95% penetrance. 
Supported in part by grants from the National Eye Institute/National Institutes of Health, EY028203 and EY019007 (Core Support for Vision Research), and unrestricted funds from Research to Prevent Blindness (New York, NY, USA) to the Department of Ophthalmology, Columbia University. 
Runhart EH, Sangermano R, Cornelis SS, et al. The common ABCA4 variant p.Asn1868Ile shows nonpenetrance and variable expression of Stargardt disease when present in trans with severe variants. Invest Ophthalmol Vis Sci. 2018; 59: 3220– 3231.
Zernant J, Lee W, Collison FT, et al. Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet. 2017; 54: 404– 412.
Zernant J, Collison FT, Lee W, et al. Genetic and clinical analysis of ABCA4-associated disease in African American patients. Hum Mutat. 2014; 35: 1187– 1194.
Lee W, Schuerch K, Zernant J, et al. Genotypic spectrum and phenotype correlations of ABCA4-associated disease in patients of south Asian descent. Eur J Hum Genet. 2017; 25: 735– 743.
Burke TR, Fishman GA, Zernant J, et al. Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2012; 53: 4458– 4467.
Maugeri A, Flothmann K, Hemmrich N, et al. The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe. Eur J Hum Genet. 2002; 10: 197– 203.
Blacharski PA. Fundus flavimaculatus. In: Newsome DA, ed. Retinal Dystrophies and Degenerations. New York: Raven Press; 1988: 135– 145.
Zernant J, Lee W, Nagasaki T, et al. Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes. Cold Spring Harb Mol Case Stud. 2018; 4: a002733.
Zhang N, Tsybovsky Y, Kolesnikov AV, et al. Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. Hum Mol Genet. 2015; 24: 3220– 3237.
Cideciyan AV, Swider M, Aleman TS, et al. ABCA4 disease progression and a proposed strategy for gene therapy. Hum Mol Genet. 2009; 18: 931– 941.
Maugeri A, van Driel MA, van de Pol DJ, et al. The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet. 1999; 64: 1024– 1035.

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