%0 Journal Article
%T Origin of pathogenic variant and mosaicism in families with a sporadic case of haemophilia B.
%A Mårtensson A
%A Letelier A
%A Manderstedt E
%A Glosli H
%A Ljung R
%J Haemophilia
%V 30
%N 3
%D 2024 May 17
%M 38632836
%F 4.263
%R 10.1111/hae.15019
%X <B>BACKGROUND: </B>Of newly diagnosed cases of haemophilia B, the proportion of sporadic cases is usually 50% of severe cases and 25% of moderate/mild cases. However, cases presumed to be sporadic due to family history may not always be sporadic. Few case reports have been published on mosaicism in haemophilia B.<BR><B>OBJECTIVE: </B>The present study aimed to trace the origin of the pathogenic variant in a well-defined cohort of sporadic cases of haemophilia B by haplotyping markers. It also aimed to determine the frequency of mosaicism in presumed non-carrier mothers.<BR><B>METHODS: </B>The study group was 40 families, each with a sporadic case of haemophilia B analysed in two-to-three generations by Sanger sequencing, haplotyping and using the sensitive droplet digital polymerase chain reaction (ddPCR) technique.<BR><B>RESULTS: </B>In 31/40 (78%) of the families, the mother carried the same pathogenic variant as her son, while Sanger sequencing showed that 9/40 (22%) of the mothers did not carry this variant. Of these variants, 2/9 (22%) were shown to be mosaics by using the ddPCR technique. 16/21 carrier mothers, with samples from three generations available, had a de novo pathogenic variant of which 14 derived from the healthy maternal grandfather.<BR><B>CONCLUSIONS: </B>The origin of the pathogenic variant in sporadic cases of haemophilia B is most often found in the X-chromosome derived from the maternal grandfather or, less often, from the maternal grandmother. Mosaic females seem to be found at the same frequency as in haemophilia A but at a lower percentage of the pathogenic variant.