Table 1.

Molecular Genetic Testing Used in Hemophilia A

Gene 1MethodProportion of Male Probands with a Pathogenic Variant 2 Detectable by Method
Severe hemophilia AModerate or mild hemophilia A
F8 Targeted analysis for intron 22 & intron 1 inversions 3~48% 40% 4
Sequence analysis 5~43%-51% 676%-99% 6
Multiplex ligation-dependent probe amplification 71.5% 80.2% 8
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on variants detected in this gene.

3.

Intron 22 and intron 1 inversions can be detected by multiple techniques (e.g., long-range PCR, inverse PCR, PCR-based "inverse shifting" procedure [Bagnall et al 2006, Rossetti et al 2008, Radic et al 2009]). Several intron 22 and intron 1 inversions have been identified; they occur following recombination between homologous sequences and can be accompanied by adjacent deletions or duplications (see Molecular Genetics).

4.

An intron 22 inversion is identified in approximately 43%-45% of individuals with severe hemophilia A [Kaufman et al 2013, Johnsen et al 2022]. An intron 1 inversion is identified in 2%-5% of individuals with severe hemophilia A [Gouw et al 2012, Johnsen et al 2022]. These inversions have not been found in individuals with moderate or mild hemophilia A.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.
7.

Multiplex ligation-dependent probe amplification (MLPA) is the most commonly used test method to detect F8 deletions and/or duplications.

8.

Deletions and duplications detected using MLPA in 2,353 males with severe hemophilia A or 1,709 males with moderate/mild hemophilia A in the My Life, Our Future project [Johnsen et al 2017]

From: Hemophilia A

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