In their paper, the authors point out the detecting mosaicism in human disease has been a challenge, as an accurate analysis must be done in the specific tissue that is harboring the variant. High-grade mosaicism (a rate of 70% and higher) is generally not detected and not assessed in clinical practice, while medium- and low-grade mosaicism are probably an underreported cause of genetic disorders. The advent of new molecular technologies, such as quantitative polymerase chain reaction (qPCR), next-generation sequencing (NGS), single-base extension assays, and droplet digital polymerase chain reaction (ddPCR), have decreased both the cost and the time required to conduct genetic testing. However, the amount of work required to quantify mosaicism is still significant, as it requires a personalized focus on each variant.
Given the time and expense involved, detecting mosaicism continues to be conducted in the research setting, and not routinely done in molecular genetic laboratories. But the authors noted that identifying mosaicism using both extrasensitive technologies and multiple types of tissue that are relatively accessible can be very informative for clinicians, carriers, and their families to help quantify the risk in prenatal counselling.
When an assessment is conducted to evaluate the risk of transmitting hemophilia, the high mosaicism rate in mothers of sporadic cases needs to be taken into account. In about 30% of sporadic cases, the mother does not appear to be a carrier. Extensive analysis of multiple tissues and extrasensitive analysis reveal that about 20% of this subgroup have mosaicism detected in somatic cells. In these cases, the mother is considered to be a carrier and prenatal diagnosis is advised. For the other 80%, the mutation will occur at conception or in the early postzygotic phase. The mother is deemed to be a noncarrier, but prenatal diagnosis can be considered or discussed.
As far as the clinical implications of mosaicism for patients, Dr Lannoy noted that they will depend on the rate of mosaicism and tissues involved. “In males, it will probably be a less severe form and no clinical symptoms in females,” she said. “In my practice of molecular diagnostics laboratory supervisor, prenatal diagnosis is proposed, even with undetectable pathogenic variant in parents, not only for hemophilia but also for other diseases such as tuberous sclerosis, Becker and Duchenne muscular dystrophy, and many others.”
Lannoy N, Hermans C. Genetic mosaicism in haemophilia: a practical review to help evaluate the risk of transmitting the disease [published online April 8, 2020]. Haemophilia. doi: 10.1111/hae.13975