They remain hidden in our genes for generations, and when they manifest themselves they cause serious ailments. Cystic fibrosis, congenital deafness and beta-thalassemia are just a few examples of the most common hereditary recessive diseases. Most people who carry them in their DNA don’t develop them and don’t know that they can pass them on to their offspring. Genetic analyses are now becoming widespread in high-risk groups for hereditary diseases (such as Ashkenazi Jews). Genetic carrier tests are already detecting the genes responsible in order to reduce the risk of transmitting these diseases to the next generation. Will we ever succeed in making them disappear?
“The advances of recent decades have led to the discovery of thousands of genes associated with these types of ailments,” says Stylianos Antonarakis, professor of Genetic Medicine at the University of Geneva (Switzerland). The genes that trigger recessive hereditary diseases show mutations compared to their variants in healthy people. The mechanism by which they are inherited is simple. When we receive the genes from our parents we do so in duplicate, that is, we obtain one copy of each gene from our mother and another from our father (except in the case of genes that are only on the Y chromosome of males). Hereditary recessive diseases are only suffered by those people who receive two copies of the harmful gene. The good thing is that this can only happen if there is the unlucky coincidence that both parents carry that mutation; the bad thing is that both parents might each have only one copy of that gene, and be carriers without knowing it.
The more than one thousand diseases of this type that we know of appear equally in men and women. They are elusive because “they are produced by alterations in genes that can be located in any of our chromosomes,” explains Judith Reina, genetic advisor in the Genomic Medicine Unit of the Dexeus Mujer Center in Barcelona (Spain). Each offspring of a pair of carriers has a 50% chance of being a carrier as well, and a 25% chance of developing the disease. From Switzerland, Professor Antonarakis adds: “In our attempt to discover new ailments with these characteristics, we looked for families where there were blood marriages. Last year we found recessive genetic blindness in children, which prevents the development of the eyes.”
The most modern tests are the so-called genetic screenings, which simultaneously detect the presence of mutated genes related to various diseases. One blood sample is enough to perform the test. “The analyses applied differ according to the centres, as well as the policies and legislative framework in each country. We have developed a specific one that allows us to detect alterations associated with more than 300 recessive diseases,” says Judith Reina. The most common method for finding mutated genes is called FISH (fluorescent in situ hybridization), and it involves using fluorescent probes designed to bind to them if they are present. Special microscopes are then used to visualize them
Although the genetic screening system is the only way to predict with high reliability the appearance of recessive genetic diseases, we are still a long way from its general application in the population. These tests are recommended in families with a prior history or in populations at risk, such as those with an origin that is Jewish, Nordic or from certain areas of the Mediterranean. People in these groups have reproduced among themselves for a long time, without the population to which they belong having incorporated external genetic material. One example is Niemann-Pick disease, which particularly affects Ashkenazi Jews in central and eastern Europe. Newborns with this metabolic disorder do not usually live more than three years. Another case is the porphyria most frequently suffered by the white population of South Africa, which results from low levels of heme, an important molecule for all the organs, leading to various ailments.
Large-scale testing of potential carriers
If the result from genetic screening is positive, carrier parents can “resort to assisted reproduction and make a pre-implantation genetic diagnosis before transferring the embryo, in order to select the one that is free of the disease,” Reina suggests. In order for comprehensive carrier detection to reduce the overall incidence of a disease, the behaviour of affected communities is crucial. For example, in recent decades, the number of children born with Tay-Sachs disease —a degenerative neurological condition that causes death before the age of five— has been reduced by 90% in the affected population of Ashkenazi Jews in the United States, thanks to selective marriages based on genetic screening.
Large-scale testing of potential carriers, accompanied by education and genetic counselling for these diseases would help reduce their incidence. Even so, “they will not disappear completely, because all human beings are carriers of some hereditary disease of a recessive nature,” Reina said.
More than half the population, 56%, exhibits genetic mutations capable of causing the main recessive hereditary diseases. The most frequent, sickle cell anaemia, affects 1 in 625 people. “Many challenges await us, such as being able to interpret the variants of some genes and incorporate the most recent discoveries into screening programmes,” concludes Antonarakis. Little by little the walls are closing in on these diseases that are hidden deep within our DNA.