Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype

Abstract

We report the results of genetic analysis on a series of 51 patients attending this Haemophilia Comprehensive Care Centre. The most common cause of severe haemophilia A--the factor VIII intron 22 inversion was detected in eight families and the factor VIII intron 1 inversion in three families. Mutation analysis was carried out on the remaining patients by nucleotide sequencing of genomic DNA after screening with conformation-sensitive gel electrophoresis (CSGE) or denaturing high-performance liquid chromatography (dHPLC). A total of 27 different FVIII non-inversion mutations were detected. Severe haemophilia was associated with 12 null mutations (six nonsense, six frameshift) and four missense mutations. A further 11 different missense mutations were associated with moderate or mild disease. To our knowledge, six null mutations [1950del 4(tttg), 3270-75insA, 4416del 10, 6735-38delA, W1029X, Y1792X] and four missense mutations (E1682K, M1947V, P2048L, P2143L) have not been previously published. Each novel missense mutation occurred at a highly conserved residue, no other candidate mutation was detected on screening the entire coding region of the FVIII gene and they were not detected in a screen of individuals without haemophilia A. The genotype-phenotype correlations of the FVIII mutations detected will be discussed.

The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype

“…The types of mutations found were in agreement with results reported in other settings (Table 2). [15][16][17][18][19][20][21][22][23][24] As expected, most of patients with severe HA carry a molecular defect predicting a null allele (large deletion, inversion, nonsense, and insertion/deletion mutations), whereas missense mutations have been found in the majority of patients with moderate (68%) and mild HA (80%).…”

Molecular genotyping of hemophilia A in Saudi Arabia: report of 2 novel mutations

“…The gene consists of 26 exons, transcribed into a 9 kb mRNA and encodes 2351 amino acids. The molecular pathology of the gene plays a determinant role in the development of the disease, different types of mutations had been reported in patients with hemophilia A [2][3][4][5][6]. Although about half of all severe factor VIII deficiencies are caused by gene rearrangements (inversions) involving intron 22 [7,8], other mutations like point mutation, large deletions and insertions have been reported in a comprehensive mutation database (URL:http://europium.csc.mrc.ac.uk/; last updated August 2007).…”

Molecular characterization of female hemophilia A by multiplex ligation-dependent probe amplification analysis and X-chromosome inactivation study

“…Indeed, she was asymptomatic with a normal level of FVIII activity (122%). Since both mutations in patient 1 are associated with severe type of hemophilia A [9], the degree of XCI skewness might not have affected the clinical manifestation. If the mutation on the Xchromosome with a residual activity is associated with mild to moderate hemophilia A, however, 92% of the skewness could result in milder clinical manifestation [10,11].…”