Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases

Abstract

One of the major questions in human genetics is what percentage of individuals in the general population carry a disease-causing mutation. Based on publicly available information on genotypes from six main world populations, we created a database including data on 276,921 sequence variants, present within 187 genes associated with autosomal recessive (AR) inherited retinal diseases (IRDs). Assessment of these variants revealed that 10,044 were categorized as disease-causing mutations. We developed an algorithm to compute the gene-specific prevalence of disease, as well as the mutational burden in healthy subjects. We found that the genetic prevalence of AR-IRDs corresponds approximately to 1 case in 1,380 individuals, with 5.5 million people expected to be affected worldwide. In addition, we calculated that unaffected carriers of mutations are numerous, ranging from 1 in 2.26 individuals in Europeans to 1 in 3.50 individuals in the Finnish population. Our analysis indicates that about 2.7 billion people worldwide (36% of the population) are healthy carriers of at least one mutation that can cause AR-IRD, a value that is probably the highest across any group of Mendelian conditions in humans.

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…Inherited forms of retinal degeneration (RD) encompass a genetically and clinically heterogeneous group of disorders estimated to cause vision impairment and loss in more than 5.5 million individuals worldwide [1,2], with 282 mapped and identified retinal degenerative disease genes documented in the RetNet human database [3]. Animal models, such as non-human primates [4], dogs [5], mice [6,7], zebrafish [8], and fruit flies [9], have been used to identify candidates for human retinal disease genes, to elucidate pathological mechanisms, and to serve as a resource for exploring therapeutic approaches.…”

Understanding the genetic architecture of human retinal degenerations

“…As mentioned above, the genetic architecture of the retinal degenerations varies among populations, not only among the broad groups analyzed by Hanany et al (5) but also in smaller subpopulations, sometimes called "special populations," which by virtue of their relatively small size and genetic isolation can be more strongly affected by founder effects, genetic drift, and as in all population groups social traditions affecting marriage patterns that lead to assortative mating, thereby elevating the consanguinity rate (6). Founder effects and genetic drift can have a major effect on allele frequencies and linkage disequilibrium, while marriage traditions can increase the frequency of To whom correspondence may be addressed.…”

“…This approach is somewhat laborious and, more importantly, requires the availability of large families segregating the disease, more common in the "special populations" discussed above who may not have the same distributions of mutations seen in the larger population groups, at least at high frequencies. The approach taken by Hanany et al (5) combines the use of large population-specific databases containing all sequence changes as well as more specific databases containing putative causative changes. Because the latter are known to misclassify some variants (especially rare ones) (8) they used a manual filtering process to examine literature reports, which should make the process significantly more robust but does not circumvent the problems of undetected variants.…”

“…Cell culture and animal models are useful in this respect, but neither they nor even induced pluripotent stem cellderived retinal organoids (11) provide a completely accurate model for the human retina. The choice of autosomal recessive diseases for the study by Hanany et al (5) provides not only an analytical advantage in identifying causative mutations but also a look at the effects of the absence of a specific gene or process on the retina and its cells without the potentially complicating gain of a deleterious function frequently seen in dominant mutations. In addition, the specific amino acids mutated in target genes allow one to identify critical parts of the protein encoded by that gene and their effect on the enzymatic or structural properties of that protein.…”

“…In addition, the presence of diseaseassociated alleles at one gene can affect the penetrance or expressivity of mutations at a second, resulting in complicated family histories and in some cases even digenic diallelic (3) or digenic triallelic (4) inheritance. In PNAS, Hanany et al (5) address this intimidating set of related diseases by developing a system to identify disease alleles at each of the associated genes and, beyond that, to calculate the gene-specific carrier frequency and the prevalence of homozygosity for variants causing autosomal recessive retinal degenerations. While appearing somewhat mundane on the surface, this work actually has far-reaching implications for both the basic science of the retina and the clinical practice of ophthalmology.…”