Figure. 1 Autosomal recessive inheritance pattern. (1)
Regarding genetic disorders, a couple with no family history may have an affected child without knowing they were asymptomatic carriers. This situation is common in related couples. It is estimated that each one of us carries at least one genetic disorder. Nevertheless, this does not mean suffering from them, as they are inherited with a recessive pattern. What does this mean? For an autosomal genetic disease with a recessive inheritance pattern to develop, it is necessary that each parental passes on one mutation to their offspring. Thus, people with only one mutation will never suffer from the disease. This way, when a couple randomly carries one mutation in the same gene the probability of having an affected baby is 25% (Figure 1). As much, related couples are more likely to be carriers of the same genetic disorder, since they probably share the same ancestral chromosomes. This scenario is more common in little cities or villages, where marriage between relatives was common not too long ago, just a few generations back. That is exactly what happened in the European royalty in the 19th and 20th centuries with Haemophilia B. This is a recessive disorder caused by a mutation in the X chromosome, which causes a bleeding disorder. Due to consanguinity marriages, the incidence of haemophilia B in the royal family was higher than in the rest of the population, which caused a great weakness in the royalty.

I AM PLANNING TO HAVE A BABY. IS THERE ANY WAY TO AVOID THIS KIND OF RISK?

Yes, there is. Scientists have developed a genetic test to detect carriers of recessive mutations, which can reduce a couple’s chances of having a child with a genetic disorder. It is known as Carrier Screening Panels, and it is performed using only a blood sample. In the first instance, only one member of the couple needs to be tested, since a negative result in one of them eliminates the possibility of having an affected child. It is important to point out that there is always a residual risk of being a carrier, since these panels do not screen for all genetic disorders. Carrier screening tests are available for a wide range number of diseases, depending on the trademark. The more expensive a panel is, the more mutations it screens. Nevertheless, there are many common diseases that can be avoided using this tool. A great example would be cystic fibrosis (CF). CF is a recessive genetic disorder that mostly affects the respiratory tract (with a variety of diverse consequences). There is no cure, and the treatment depends on the case, being 37 the average life expectancy for patients who live past childhood (2). There are a lot of CF healthy carriers worldwide who do not know their carrier status and are at risk of having a child affected by this condition.

WHAT ARE THE MAIN CONSIDERATIONS WHEN SCIENTIST CHOOSE THE GENETIC DISEASES FOR THEIR COMMERCIAL PANEL?

  • Ethnicity. Some autosomal recessive disorders are more common in people of specific ethnic backgrounds. Following the example of Cystic Fibrosis, the ethnicity-specific data for individuals with no history of Cystic Fibrosis referred for carrier screening is 1 in 28 for Caucasian, 1 in 70 for Native American, 1 in 84 for African American and 1 in 242 for Asian (3). For this reason, it is recommended that ethnicity is considered when selecting the screening panel. Table 1 summarizes the most common autosomal recessive diseases based on the population.
  • Gender. Since women carry two X chromosomes and men only one, it is important to screen the X chromosome. Thus, if a woman carries one mutation in one of her X chromosomes, she has a second one to supply the “defective gene”. In turn, if a man carries a mutation in his only X chromosome, he will suffer from the disease, since he does not have another X chromosome to compensate the mutation (a situation known as ‘hemizygosis’). A great example of this kind of genetic disorder is Duchenne muscular dystrophy (DMD). The responsible mutation for this genetic disorder is located on the X chromosome. This way, a woman carrying a mutation on her X chromosome is totally asymptomatic and all her female children will not suffer from DMD. However, regarding male children, they have a probability of 50% of developing the disease (Fig. 2).

Figure 2. X-linked recessive disorders inheritance (4).
Table 1. Most common autosomal recessive diseases based on the population (5).

WHAT IF MY PARTNER AND I ARE BOTH CARRIERS OF THE SAME GENETIC DISORDER?

If both members of a couple are carriers for the same recessive genetic disorder, they have a chance of 1 in 4 of having a baby affected of this disease, or 1 in 2, if it is the case of an X-linked recessive trait. Fortunately, there are other alternatives for them:

  • Preimplantational Genetic Test for Monogenic diseases (PGT-M). For PGT to develop it is necessary to perform an in vitro fertilization cycle. After some days of stimulation, eggs are collected and fertilized by embryologists. Then, after three or five days of culture, embryos are biopsied, which means removing a little sample of each embryo to assess their condition: affected or unaffected. Only those unaffected embryos would be eligible to be transferred to the woman’s uterus in order to achieve a healthy pregnancy.
  • Gamete donor. A gamete donor should also be screened for at minimum the same genetic disorder that is being considered within the treatment. If the donor is a carrier of the same disease it is necessary to look for another donor.

TAKE HOME MESSAGE

Everybody carries at least one genetic disorder. Since carriers are usually healthy, they are not aware of their risk of having a child with a genetic disorder. Carrier screening tests are aimed at minimizing the random risk each couple have because of being carriers of the same recessive genetic condition. This test consists of a panel that screens a variable number of mutations and genetic disorders depending on the commercial name. By performing a carrier screening test a couple can minimize the risk of having an affected child, but remember that commercial panels only screen for the most common genetic disorders.

If you are planning to have a baby and are interested in carrying out a Carrier Screening test, you should speak with your gynaecologist and seek for advice on these matters.

REFERENCES

  1. https://geneticsupportfoundation.org/archive/genetics-and-you/autosomal-recessive-inheritance
  2. https://cysticfibrosisnewstoday.com/cystic-fibrosis-life-expectancy/
  3. Rohlfs EM, Zhou Z, Heim RA, Nagan N, Rosenblum LS, Flynn K, et al. Cystic fibrosis carrier testing in an ethnically diverse US population. Clin Chem. 2011;57(6):841–8.
  4. http://www.treat-nmd.eu/dmd/about/x-linked-recessive/
  5. Gabriel A. Lazarin et al.  An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals Genet Med. 2013 Mar; 15(3): 178–186.