Spectrum and origin of mutations in sporadic cases of haemophilia A in China

Abstract

The spectrum of F8 genetic variants identified in sporadic families was fairly diverse. The high prevalence of chimaeras in carriers suggests that more cautions should be taken in genetic counselling of sporadic haemophilia families.

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

“…This means that, if a pathogenic Inv22 is identified in a ‘sporadic patient’, 98% of mothers are carriers whose origin is the male germline of the maternal grandparent 26 . This hypothesis was, however, revised in the publications of Oldenburg et al and Lu et al, who demonstrated that the Inv22 pathogenic variant is not restricted to meiotic cell divisions but also occurs upon mitotic cell divisions, either in germ cell precursors or somatic cells 27,28 …”

“… 3‐4,23,34 In de novo sporadic maternal or grandmaternal cases, 1/5 was tested as a mosaic mother in the Swedish and 9/40 in the Chinese studies, using sensitive methods for somatic mosaicism. In the latter study, the authors were surprised to detect a relatively high proportion of de novo Inv22 at mosaic state in the patients’ mothers (3/10 mothers tested), as this contrasts with the view that Inv22 exclusively occurred upon the meiosis of gametes, predominantly in spermatozoa 24,28 . Whereas only very few publications of large studies are available in haemophilia B, somatic mosaicism has been regularly reported, suggesting this biological phenomenon is not a rare event in haemophilia B 13‐14,22,35 (Table 1).…”

“…Nearly 70% of mothers of sporadic haemophilia patients exhibit a carrier status, which means the pathogenic variant can be identified in DNA extracted from all tissues, such as leucocytes, buccal brushings, hair root bulbs, urothelial cells and germ cells 28 (Figure 3).…”

The characteristics and spectrum of F9 mutations in Chinese sporadic haemophilia B pedigrees

“…The mosaicism of the F9 gene variants were determined by ABI PRISM SNaPshot ddNTP Primer Extension kit as described before. 10 The mutant/wild allele was first amplified by common primer and then was used as template for a second round of PCR using ddNTP labelled with a different fluorescent group. The PCR amplification proceeded with specific extension primer with ddNTP incorporated into the PCR product.…”

Review of molecular mechanisms at distal Xq28 leading to balanced or unbalanced genomic rearrangements and their phenotypic impacts on hemophilia

“…22 Several HA studies have reported somatic mosaicism of Inv22 in females, indicating that the Inv22 could also derive from mitotic cell divisions, though this remains rare. [23][24][25]…”