Hemophilia is an umbrella term for a rare and hereditary group of disorders that alter the body’s normal blood coagulation. Caused by a range of variants in the F8 (Xq28) or F9 (Xq27.1) genes, which are both located on the X chromosome, hemophilia presents as 1 of 2 predominant types: hemophilia A and hemophilia B. Hemophilia A’s X-linked trait manifests as a congenital absence or decrease in plasma clotting factor VIII, while hemophilia B is caused by an X-linked mutation in coagulation factor IX (FIX). Both hemophilia A and B are associated with an inheritance pattern in which the phenotype is primarily expressed in males who are hemizygous for a gene pathogenic variant. Recent studies also suggest that about 30% of female carriers have a higher risk of bleeding that is similar to that of a patient with mild hemophilia.

As 70% of hemophilia A and B cases have a family history, the prevalence of sporadic disease is estimated at 30%. The term sporadic is used to define cases without a family history of the disease and when the index case is designated as the “first affected sibship“ in that family, although it can cause confusion. Referring to a ‘sporadic case’ can mean 1 of 3 different possibilities: a de novo pathogenic variation occurs in the fetus during pregnancy and the mother is not a carrier, the mother is a carrier but the index case in the first case in the family, or a carrier who has not inherited the hemophilia-causing variant.

However, study results have suggested that 70% of the mothers of seemingly sporadic cases are carriers. For the remaining 30%, including some who do not appear to be carriers, the pathogenic variant has been detected as low somatic and gonosomal mosaicism.

A review paper published in Haemophilia examines the different kinds of mosaicism observed in hemophilia, the mechanisms by which they arise, and the risk of passing these variants along to offspring.

“Genotype analysis should be offered to all obligate carriers of hemophilia and ‘at-risk’ or potential carriers of hemophilia,” said the paper’s co-author Nathalie Lannoy, PhD, from the division of adult haematology, Haemophilia Center, Université Catholique de Louvain in Belgium, in an interview with Hematology Advisor. “For all obligate and genetic confirmed females, prenatal diagnosis may be offered to define status of all male [fetuses] in order to guide the management of the delivery or to terminate the pregnancy in case of an affected male fetus.”’

She also noted that the mothers of all “first affected case in the family” patients, should be tested for the previously identified genetic variant in the F8 and F9 genes. “Even when the pathogenic variant is not identified in DNA [from] leucocytes or other somatic tissues – [which] is true in 80% [of sporadic cases with noncarrier mother status] – prenatal diagnosis may be offered in [the] case of male fetus,” Dr Lannoy explained.

A fairly common event in human genetic disorders, mosaicism refers to the presence of genetically distinct cells within an organism that result from postzygotic mutational events. The significance of mosaic pathogenic variants has remained poorly defined as conventional technology, including Sanger sequencing, has not proven sufficiently sensitive for detecting low-level somatic mosaicism. But using DNA extracted from all tissue types, including leukocytes, buccal brushings, hair root bulbs, urothelial cells, and germ cells, along with extrasensitive molecular testing methods, have now made it easier to detect both single-nucleotide variants (SNVs) and copy-number variants (CNVs) at a mosaic level in parents.