Phenotypic effects of balanced X-autosome translocations in females: a retrospective survey of 104 cases reported from UK laboratories

Waters, Jonathan J.; Campbell, Paul L.; Crocker, Amanda; Campbell, Carolyn M.

doi:10.1007/s004390100465

Cited by 52 publications

(41 citation statements)

References 34 publications

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“…This can lead to the expression of X-linked recessive disorders in heterozygous women if the derivative X-chromosome harbours a recessive disease allele or if the translocation disrupts a disease causing gene. 19 We have determined by standard cytogenetic analyses that the most extremely skewed girl (III.9) has a normal karyotype (data not shown), and by tiling path array CGH (SMRT v2) at submegabase resolution that no amplifications or deletions are present (data not shown). Thus, the dramatically skewed XCIRs in this family are unlikely to be due to chromosomal abnormalities.…”

Section: Resultsmentioning

confidence: 99%

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

et al. 2007

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Factor VIII gene, F8, mutations cause haemophilia A (HA), an X-linked recessive disorder. Expression in heterozygous females has been ascribed to skewed X-chromosome inactivation (XCI). To investigate the cause of HA in three heterozygous females within an Atlantic Canadian kindred, the proband (severely affected girl, FVIII activity: 2%) and 17 relatives across three generations were studied. F8 genotype, FVIII activity, XCI ratio (XCIR) (paternal active X: maternal active X), karyotype, submegabase resolution tiling set array competitive genome hybridization (competitive genomic hybridization (SMRT)), and microsatellite analyses were utilized. A positive linear relationship between FVIII activity and percentageactivated normal X-chromosome was found in HA heterozygous females (R 2 ¼ 0.87). All affected, but no unaffected females, had an XCIR skewed toward activation of the mutant X-chromosome (proband 92:8, SD 2). Unexpectedly, high numbers of females have dramatically skewed XCIRs (480:20 or o20:80) (Po0.05). The distribution of XCIR frequencies within this family was significantly different than predicted by normal population data or models of random XCI (Po0.025), with more females having higher degrees of skewing. Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, and X-inactive-specific transcript mutations, are not consistent with our results. This study shows that FVIII activity in HA heterozygous females can be directly related to XCI skewing, and that low FVIII activity in females in this family is due to unfavourable XCI skewing. Further, the findings suggest that these XCI ratios are genetically influenced, consistent with a novel heritable human X controlling element (XCE) functioning similarly to the mouse Xce.

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Section: Resultsmentioning

confidence: 99%

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

et al. 2007

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“…However, infertility because of gonadal dysgenesis is not uncommon among women with a breakpoint in the critical region Xq13 → q27 (a narrow region within Xq22 is not critical, Therman et al, 1990). In a UK collaborative study of 104 females with X-autosome translocations Waters et al (2001) described the phenotype in about one-third of all carriers with early age of menopause (before the age of 40) through to primary amenorrhea. Therapy of sterility because of manifested premature ovarian failure is difficult.…”

Section: X-autosome Translocation In the Femalementioning

confidence: 99%

Somatic chromosomal abnormalities in infertile men and women

Mau-Holzmann¹

2005

Cytogenet Genome Res

130

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Infertility – the inability to achieve conception or sustain a pregnancy through to live birth – is very common and affects about 15% of couples. While chromosomal or genetic abnormalities associated with azoospermia, severe oligozoospermia or primary ovarian failure were of no importance for reproduction prior to the era of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), advances in assisted reproductive techniques (ART) now enable many infertile couples to have children. These developments have raised the question of the genetic consequences of ICSI: concerns of the potential harm of the invasive procedure and concerns about the genetic risk. The infertile male and female definitely have an increased risk to carry a chromosomal abnormality. Detection of such an abnormality is of fundamental importance for the diagnosis of infertility, the following treatment, the evaluation of the risk for the future child and the appropriate management of the pregnancy to be obtained. Therefore, cytogenetic screening of both partners is mandatory prior to any type of ART. The present review is based on several surveys on male and female infertility and analyzes the types and frequencies of the different reported chromosome abnormalities according to the type of impairment of spermatogenesis and the type of treatment planned or performed. With regard to assisted reproductive techniques (especially ICSI) the main types of chromosomal abnormalities are discussed and their potential risks for ICSI. If available, reported cases of performed ICSI and its outcome are presented. The detection of an abnormal karyotype should lead to comprehensive genetic counselling, which should include all well-known information about the individual type of anomaly, its clinical relevance, its possible inheritance, the genetic risk of unbalanced offspring, and the possibilities of prenatal diagnosis. Only this proceeding allows at-risk couples to make an informed decision regarding whether or not to proceed with ART. These decisions can be made only when both partners have clearly understood the genetic risks and possible consequences when ART is used.

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“…In a report of a 104 cases from the UK, Waters et al found in the majority of the cases the normal X-chromosome was preferentially inactivated, supporting the concept that either functional autosomal monosomy or X disomy may give rise to an abnormal phenotype and therefore is naturally avoided [13].…”

Section: Discussionmentioning

confidence: 85%

Breakpoint of a balanced translocation (X:14) (q27.1;q32.3) in a girl with severe hemophilia B maps proximal to the factor IX gene

Paola

Goldman

Qian

et al. 2004

Journal of Thrombosis and Haemostasis

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Summary. Hemophilia B is an X‐linked bleeding disorder caused by the deficiency of coagulation factor (F)IX, with an estimated prevalence of 1 in 30 000 male births. It is almost exclusively seen in males with rare exceptions. We report a girl who was diagnosed with severe (<1%) FIX deficiency at 4 months of age. Cytogenetic studies in the patient showed a balanced translocation between one of the X‐chromosomes and chromosome 14, with breakpoints at bands Xq27.1 and 14q32.3. Both parents were found to have normal chromosomes. Late replication studies by incorporation of 5‐bromodeoxyuridine showed non‐random inactivation of the normal X‐chromosome, a phenomenon frequently seen in balanced X/autosome translocations. To map the breakpoint, fluorescent in‐situ hybridization was performed. A PAC DNA probe, RP6‐88D7 (which contains the FIX gene) hybridized only on the normal chromosome X as well as onto the derivative 14. Using a PAC DNA probe, RP11‐963P9 that is located proximal to the FIX gene, we obtained signals on the normal and derivative X and also on the derivative 14. We conclude that the breakpoint is located within the DNA sequence of this clone mapping proximal to the FIX gene. Since the FIX gene seems to be intact in the derivative 14, the breakpoint may affect an upstream regulatory sequence that subjects the gene to position effect variegation (PEV).

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Phenotypic effects of balanced X-autosome translocations in females: a retrospective survey of 104 cases reported from UK laboratories

Cited by 52 publications

References 34 publications

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

Somatic chromosomal abnormalities in infertile men and women

Breakpoint of a balanced translocation (X:14) (q27.1;q32.3) in a girl with severe hemophilia B maps proximal to the factor IX gene

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