Recent sequencing of personal genomes has shown that, out of the many non-synonymous variants identified 
, on average every individual is an unaffected carrier of 10–20 recessive alleles for Mendelian conditions 
. Our finding experimentally that 1 in 4–5 individuals from the general world population could be a carrier of mutations linked to hereditary blindness confirms and extends previous theoretical estimates on HRD genetic epidemiology 
. Furthermore, our measurements represent a significant underestimation of the real frequency, considering that no mutations other than definite null changes were considered and that known HRD genes account for only 50–70% of the diagnosed cases 
. According to the data reported in the Human Gene Mutation Database 
for the 106 genes analyzed, the average ratio between null and missense mutations is 1 to 0.87. If we use this proportion to roughly extrapolate our findings and take missense mutations into consideration, the frequency of unaffected carriers would be 1 in 2.5 individuals. Further extrapolation to patients with HRD who are negative for mutations in known genes (assumed to represent 30% of all recessive cases, based on data from retinitis pigmentosa 
) would lead to the even more dramatic figure of 1 unaffected carrier in 1.7 individuals.
The “aggregate frequency of mutations” of a genetically heterogeneous Mendelian disorder can show significant disparity with our knowledge of “disease frequency” or prevalence, which may be confusing at times. This is because the aggregate frequency is strongly influenced by the number of genes and percent of cases that can be attributed to each gene, which are unique to every genetic condition. Diseases like HRD, displaying high genetic heterogeneity and a relatively even contribution for each gene, show in general high aggregate frequency despite a low overall prevalence 
Such an elevated frequency of unaffected carriers of HRD mutations has fortunately a limited influence on the likelihood of generating affected offspring (i.e. 1/6,000, on average), since the chance for two unrelated parents to carry each a heterozygous mutation in the very same gene remains low. However, it has a few consequences for both genetic counseling and research, especially in our age of full genome or exome sequencing. First, it is likely that, in addition to causative mutations, other HRD alleles could be accidentally present in patients with retinal diseases. Misinterpretation of such findings could complicate molecular diagnoses or give rise to false speculations about oligogenic inheritance or dominant effects of recessive alleles. A second consequence is that variation databases from cohorts of healthy individuals, routinely used as negative controls for suspected HRD variants in molecular testing, may in fact contain true mutations.
Most important, a high frequency of HRD mutation carriers translates into a quite increased risk for a consanguineous couple of generating a child with a blinding disease. This phenomenon is particularly evident in populations displaying an elevated degree of inbreeding 
, for which the prevalence of hereditary blindness is higher than the average 
. In such a context, any recessive mutations in any HRD genes that would be present in both parents could be easily brought to homozygosity in the offspring, without benefiting from the buffering effect of genetic heterogeneity.