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 extra‐sensitive 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.