Comprehensive genomic filtering algorithm to expose the cause of skewed X chromosome inactivation. The proof of concept in female haemophilia expression.

Background: Exploring the expression of X linked disorders like haemophilia A (HA) in females involves understanding the balance achieved through X chromosome inactivation (XCI). Skewed XCI (SXCI) may be involved in symptomatic HA carriers. We aimed to develop an approach for dissecting the specific cause of SXCI and verify its value in HA.

Molecular insights into the mechanism of nonrecurrent F8 structural variants: Full breakpoint characterization and bioinformatics of DNA elements implicated in the upmost severe phenotype in hemophilia A.

Hemophilia A (HA) provides excellent models to analyze genotype-phenotype relationships and mutational mechanisms. NhF8ld's breakpoints were characterized using case-specific DNA-tags, direct- or inverse-polymerase chain reaction amplification, and Sanger sequencing. DNA-break's stimulators (n = 46), interspersed repeats, non-B-DNA, and secondary structures were analyzed around breakpoints versus null hypotheses (E-values) based on computer simulations and base-frequency probabilities.

Inverse PCR to perform long-distance haplotyping: main applications to improve preimplantation genetic diagnosis in hemophilia.

Among other applications of long-distance haplotype phasing in clinical genetics, determination of linked DNA markers as surrogate for problematic structural variants (e.g., repeat-mediated rearrangements) is essential to perform diagnosis from low-quality DNA samples.