X-Autosome Translocations

 

Epidemiology and Etiology:

·         All de novo balanced X-autosomal translocations studied thus far have been of paternal origin

·         May reflect “availability” in male meiosis of the X chromosome for exchange with other chromosomes

·         All familial X-autosomal translocations must be transmitted by females

·         Males are infertile

 

Common sites:

·          

 

Gross features:

·          

 

Histologic features:

·          

 

Immunophenotype:

Marker:

Sensitivity:

Specificity:

 

 

 

 

Molecular features:

·         X inactivation is typically non-random

·         secondary selection effect

·         random X-inactivation is correlates well with an abnormal phenotype

·         in the case of a balanced translocation

·         the normal X is preferentially inactivated (skewed inactivation)

·         but not so in ~25% - distal Xp and Xq translocations usually

·         de novo translocation:

·         Mechanisms of possible imbalance:

·         Submicroscopic deletion or duplication at one of the breakpoints

·         translocation site results in disruption of a gene, this will result in manifestation of an X-linked trait normally only observed in affected males

·         2/18 (11%)

·         Xp21 – Duchenne muscular dystrophy – large locus

·         Position effect

·         Disrupted pairing at meiosis

·         Xq13-q22 or Xq22-q26

·         20-40% risk of gonadal dysgenesis / premature ovarian failure (POF)

·         primary amenorrhea

·         premature menopause

·         in the case of an unbalanced translocation:

·         generally the translocation product containing the X inactivation centre is present

·         this derivative chromosome is generally (“invariably”) inactivated

·         this minimizes the clinical consequences

·         inactivation spreads onto translocated autosomal segment to an extent

·         less extensive than on native X

·         discontinuous

·         a specific locus can be affected differently by one translocation than in another

·         X-inactivation pattern ascertained in CVS is not representative of the fetus?

·          

 

Other features:

·         Fetus with X-autosome translocation:

·         balanced translocation:

·         inherited (mother):

·         female fetus:

·         not necessarily the same phenotype as that of the mother

·         X-inactivation status may or may not be helpful

·         male fetus:

·         too little information about this for any firm advice to be offered

·         some have been normal (but infertile), some have had major genital defect

·         de novo translocation:

·         44% risk (n=18) of fetal abnormality in prenatal diagnosis

·         Much higher than 6.7% risk in autosomal reciprocal translocations

·         if a female manifests an X-linked phenotype normally seen only in males, high-resolution chromosome analysis is indicated

·         Breakpoints disrupting X-borne loci

·         Females may manifest X-linked Mendelian disorders

·         Ex. Duchenne/Becker muscular dystrophy

·         May be direct disruption of gene or “position effect”

·         unbalanced translocation:

·         with X deletion:

·         Turner or partial Turner syndrome in some

·         With X duplication:

·         Incomplete Klinefelter in a male

·         Diminished 47,XXX in a female

·         Areas of autosomal trisomy may be functionally silent due to inactivation

·         But this is variable and unpredictable

·         Probability of abnormality is high

·         Parent with an X-autosome translocation:

·         Risk of an unbalanced offspring:

·         Female carrier:

·         Substantial risk of abnormality (20-40%)

·         Abnormality ranges from mild (partial Klinefelter, partial X trisomy) to severe (partial X disomy or autosomal aneuploidy)

·         Each translocation needs to be considered separately

·         Male carrier:

·         No risk (infertile)

·         Infertility:

·         male  carriers almost invariably have infertility

·         due to spermatogenic arrest, mostly at pachytene stage of meiosis I

·         mechanism is presumed to be disruption of the sex vesicle

·         female carriers: ~50% are infertile

·         female carriers have risk of gonadal dysgenesis:

·         breakpoints at 2 “critical regions” is characteristically associated with gonadal dysgenesis in women (POF or primary amenorrhea) (but some are still fertile)

·         Xq13-q22

·         Particularly Xq13.3-q21.1

·         Xq22-q27

·         Particularly Xq26.1-q27

·         Separated by a narrow region within Xq22 that is not critical

·         Mechanism of this effect is not likely due to actual disruption of genes

·         Impairment of X chromosome activity in meiosis or mitosis is one theory

 

References:

·         Gardner RJM, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. 2nd ed. Oxford University Press, USA; 1996.

·         Gardner & Sutherland, 3rd ed. (2004)

·         Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 7th ed. Saunders; 2007.

·         Wutz A, Gribnau J. X inactivation Xplained. Curr. Opin. Genet. Dev. 2007;17(5):387-93.

·         Tsai C, Rowntree RK, Cohen DE, Lee JT. Higher order chromatin structure at the X-inactivation center via looping DNA. Dev. Biol. 2008;319(2):416-25.

·         Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature. 1961;190:372-3.

·         Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434(7031):400-4.

·         Brown CJ, Greally JM. A stain upon the silence: genes escaping X inactivation. Trends Genet. 2003;19(8):432-8.

·         Abrams L, Cotter PD. Prenatal diagnosis of de novo X;autosome translocations. Clin. Genet. 2004;65(5):423-8.

·         Heard E. Recent advances in X-chromosome inactivation. Curr. Opin. Cell Biol. 2004;16(3):247-55.

·         Avner P, Heard E. X-chromosome inactivation: counting, choice and initiation. Nat. Rev. Genet. 2001;2(1):59-67.