Genetic mosaicism in haemophilia: A practical review to help evaluate the risk of transmitting the disease

Abstract

Approximately 70% of patients with haemophilia exhibit a clear inheritance pattern, while for the remaining 30%, patients are the first to be diagnosed in their family and are considered sporadic cases. In such a setting, the determination of carrier status and the risk estimation of disease transmission to another child are major challenges for genetic counselling. Large studies have suggested that genetic testing reveals 70% of sporadic patients' mothers are carriers. In the remaining 30%, in some apparently non-carrier mothers, the pathogenic variant can be detected as low somatic and gonosomal mosaicism. The significance of mosaic pathogenic variants has thus far been underestimated, since conventional Sanger sequencing and other technology are not sufficiently sensitive. The study of various tissue samples and recent extrasensitive molecular methods have now made it easier to detect both single-nucleotide variants (SNVs) and copy-number variants (CNVs), at a mosaic level in parents, and to predict the probability of disease recurrence. This review seeks to examine various kinds of mosaicism in haemophilia, including the mechanisms by which they arise and the risk of passing these variants on to the next generation. In addition, we focus on the selection of cell tissues and methods to detect these mosaic variants in the haemophilia setting. Taking into account the high rate of mosaicism in mothers of sporadic cases, we propose a diagnostic flow chart that could facilitate better evaluation of the risk of transmitting haemophilia in genetic and prenatal counselling. K E Y W O R D S

Genetic analysis for carrier diagnosis in hemophilia A and B in the Mexican population: 25 years of experience

“…The significant proportion of sporadic cases (47%) agrees with that reported in Argentinian families (53%), and among the Inv22 positive families, 50% were sporadic (De Brasi et al, 2000; Mårtensson et al, 2016). The significant proportion of de novo pathogenic variants (3/23 of SHA positive to F8 inversions, 13%) along with the negative result in the probands' mothers recalls the probability of mosaicism reported in the literature (Kasper & Lin, 2007; Lannoy & Hermans, 2020). (Kasper & Lin, 2007).…”

“…We present the diagnosis of 40 carriers and 73 noncarrier cases for Mårtensson et al, 2016). The significant proportion of de novo pathogenic variants (3/23 of SHA positive to F8 inversions, 13%) along with the negative result in the probands' mothers recalls the probability of mosaicism reported in the literature (Kasper & Lin, 2007;Lannoy & Hermans, 2020). (Kasper & Lin, 2007).…”

Diagnosis of De Novo Mosaic Balanced Translocation t(1;3)(q42;q25) in a Fetus Conceived Using Pre-implantation Diagnosis Due to Presence in the Father of a Different Balanced Translocation

“…As indicated in Figure 3, an apparently STR result showed that one paternal allele and one maternal allele were found at all loci. Considering that the mosaicisms proportion of our case was close to 50% in both amniotic uid cells and umbilical cord blood, the mechanism of BRTM in our case was plausible due to a de novo mitotic error may originate in a zygote within the rst or early cell divisions, which results in a mosaic embryo with the variant present in a half proportion of cells, and this mosaicism can affect somatic and/or gonadal tissues 20 .However, due to the growth deviation of different cell types in the process of cells culture, the mosaic ratio of different fetal tissues may be different.…”

Current therapeutic approaches in the management of hemophilia—a consensus view by the Romanian Society of Hematology

“…Measurement of FVIII from cord blood of male babies with mothers who carry the hemophilia gene is recommended immediately after birth. In this case there are no risks for the baby (5,39). A timetable illustration of when genetic testing can take place is found in Figure 2.…”

“…In approximately 30% of sporadic cases (i.e., no known family history of hemophilia), the variant (mutation) causing the disease cannot be found in the mother. However, with the conventional Sanger sequencing, carriership cannot be conclusively ruled out since she may be a mosaic not detected by this technique (39).…”