Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A

Abstract

This study describes the genetic mechanisms responsible for the de novo occurrence of severe and mild hemophilia A in monozygotic twin females. Both twins were found to carry a previously known factor VIII mutation (Tyr16Cys) in the heterozygous state which most probably arose in the paternal germ line. Both twins showed concordant skewing of X inactivation toward the maternally derived normal X chromosome, the most severely affected twin exhibiting a higher percentage of inactivation of the normal X chromosome. The degree of skewing of X inactivation closely correlated with both the coagulation parameters and the clinical phenotype of the twins. Since these twins were monochorionic, such results suggest that the twinning event in this case has occurred after the onset of the X-inactivation period. IntroductionHemophilia A is an X-linked recessive bleeding disorder caused by deficiency of factor VIII (FVIII) which occurs in 1/5000 male births. 1 Clinical severity is inversely related to residual factor VIII activity (FVIII:C) such that patients with less than 1%, 1%-5%, and 5%-30% FVIII:C are classified as severe, moderate, or mild, respectively. The molecular basis underlying hemophilia A is well characterized, and about half of severely affected individuals have large genomic inversions disrupting the FVIII gene (F8). [2][3][4] In the remaining cases, different heterogeneous point mutations, insertions, and deletions are found scattered throughout the 26 exons, as well as in the introns of F8. 5 Hemophilia A is transmitted by heterozygous females denoted as carriers, who are generally asymptomatic since random X inactivation results in approximately equal proportions of somatic cells in which either the normal X or the mutated X chromosome is active. 6 Even though the disease in females is extremely rare, a few cases have been documented, resulting from different pathophysiologic mechanisms. [7][8][9][10][11][12][13] Here, we report monozygotic (MZ) twin girls both carrying the same F8 mutation which results in severe hemophilia A in one twin and mild phenotype in her co-twin. Although they exhibited a different clinical and biologic severity, they both showed concordant skewing of X inactivation toward the normal X chromosome. In this respect, they differed from some pairs of MZ twin females who typically showed a "mirror-image" pattern of X inactivation. As the twins were classified as monochorionic (MC) at birth, our data strongly support the hypothesis that the splitting event in MC-MZ twin pairs occurs after the onset of X-inactivation period. Study design Case reportThe family is presented in Figure 1. Coagulation studies showed FVIII:C of less than 1% for proposita II.2 and 12% for II.3 on repeated measurements, with normal VWF:Ag and VWF:RCo levels in both cases. None of the other family members (I.1, I.2, and II.1) exhibited hemophilia or had abnormal values of plasma FVIII:C and von Willebrand factor (VWF), suggesting an absence of familial inheritance for the disease. Binding of FVIII to VWF was fo...

Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review

“…A new explanation proposed by Monteiro et al . [65] is that monochorionic MZF is, in fact, a heterogeneous group that differs in the timing of the twinning event after the onset of X-inactivation [59]. …”

Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A

“…Some have cytogenetic abnormalities such as X/autosome translocations. 4 Some are monozyotic twins 5 who are often discordant for a variety of X-linked disorders because of an unexplained disturbance in the randomness of X inactivation in twins. 6 Others are isolated cases of females who are heterozygous for an F8C mutation, but whose mutant gene is expressed in more than the 50% of cells expected based on random X inactivation.…”

Discordance for X-Linked Hypophosphataemic Rickets in Identical Twin Girls

“…There are several reports of twins discordant for X-linked recessive disorders including muscular dystrophy [26], colour blindness [27], fragile X syndrome [28], haemophilia [29] and Lesch-Nyhan disease [30]. All of these cases have been shown to be due to skewed X inactivation in the affected twin, preferentially inactivating their ‘normal’ X and thus producing affected females of an X-linked recessive disorder.…”