First, the title: “Monoallelic
ABCA4 Mutations Appear Insufficient to Cause Retinopathy: A Quantitative Autofluorescence Study,” is confusing. Because all diseases caused by mutations in the
ABCA4 gene are recessive (i.e., require mutant
ABCA4 alleles on
both chromosomes for an expression of a phenotype), the carriers of
ABCA4 alleles are, by genetic definition, asymptomatic. The argument of Müller et al.
1 in the introduction, that “there has been an ongoing debate on whether or not monoallelic
ABCA4 mutations might also cause disease at the benign end of the spectrum of ABCA4-related retinopathy,” is incorrect, because there has been no such debate. What has been debated is whether
ABCA4 carriers are
more susceptible to AMD. Regardless the status of that debate, it has never been suggested that carrying one
ABCA4 pathogenic allele alone will result in a disease phenotype. Age-related macular degeneration is a complex trait that, by definition, suggests that a combination of many alleles in many genes, together with environmental factors, cause the late-onset disease. It is therefore clear that one mutation in one gene cannot cause AMD; if this were correct, then we would be dealing with a case of late-onset dominant Mendelian trait with reduced penetrance. This is exactly the case with the
TIMP3 gene, in which dominant (i.e., single) mutations cause Sorsby macular dystrophy
3 and also, as most recently shown,
4 cause the disease at an advanced age, thereby confusing the phenotype with AMD. “Causing a disease” and “increasing disease susceptibility” are two different terms describing very different disease mechanisms.