The intron 22 inversion found in up to 50% of severe hemophilia A patients results from a recombination between three intron 22 homologous copies (int22h). This study evaluated the implication of these copies in the formation of extended duplications comprising exons 1-22 of the factor 8 (F8) gene and their association with hemophilia and mental retardation. Two hemophilic patients with moderate and severe phenotypes and a third nonhemophilic patient with developmental delay were studied. All exhibited a duplication of F8 gene exons 1-22 identified by multiplex ligation-dependent probe amplification along with abnormal patterns on Southern blotting and unexpected long-range PCR amplification. Breakpoint analysis using array comparative genomic hybridization was performed to delimit the extent of these rearrangements. These duplications were bounded on one side by the F8 intragenic int22h-1 repeat and on the other side by extragenic int22h-2 or int22h-3 copies. However, the simultaneous identification of a second duplication containing F8 gene exons 2-14 for the moderate patient and the classical intron 22 inversion for the severe patient are considered in this study as the genetic causal defects of hemophilia. This study shows that the well-known int22h copies are involved in extended duplications comprising F8 gene exons 1-22. These specific duplications are probably not responsible for hemophilia and intellectual disability, but should be carefully considered in genetic counseling, while continuing to investigate the causal mutation of hemophilia.
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
Among 23 germline mutations identified in the APC screening of 45 familial adenomatous polyposis (FAP) patients, we have found 10 different novel frameshift mutations in 11 apparently unrelated patients. In two cases, an additional missense mutation was detected. One previously described as a causative germline mutation (S2621C), associated with a 1-bp insertion (4684insA) on the opposite allele, did not segregate with the FAP phenotype in the family and was therefore considered as being non-pathogenic. The other (Z1625H) was located 2 codons before a 1-bp deletion (4897delC). Both mutations were transmitted together from an FAP father to his affected son. The FAP phenotype of these 10 novel truncating mutations was clinically documented within their kindreds. Important variability was observed in the phenotype. Interestingly, we noted that a mutation (487insT) localized at the boundary of the 5' attenuated APC phenotype region in two unrelated families resulted in classical polyposis. A clear-cut genotype-phenotype correlation could be drawn in only two instances. In one family, a 4684insA mutation led to a mild polyposis associated with early inherited osteomas and, in the family bearing the double mutation (Z1625H + 4897delC), the phenotype was obviously a 3' attenuated type. Our data illustrate the wide genetic and phenotypic heterogeneity of this condition between and within the families, making the establishment of correlations complex and any prediction in this disease difficult, although targeting the mutation site may be helpful in some specific cases.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.