China
Africa
Explore chapters and articles related to this topic
Genetic Counseling in Assisted Reproductive Technology
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Patients should be counseled about the recurrence risks of the condition for which they are pursuing testing. This corresponds to the inheritance pattern of the condition: 50% for autosomal dominant conditions and 25% for autosomal recessive conditions. For X-linked conditions, the appropriate recurrence risks to quote will depend on whether the female carriers are generally expected to be affected: 50% for X-linked conditions classified as dominant and 25% for X-linked conditions classified as recessive. Even when the condition is considered to be classically recessive, patients should be cautioned about the chance of female carriers manifesting the condition due to skewed X-inactivation.
Aicardi Syndrome and Klinefelter Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Skewed X-inactivation refers to the preferential, non-random inactivation of one of the two X chromosomes in females. While random X-inactivation keeps each X chromosome active in about half of cells, skewed X-inactivation keeps one X chromosome active in more than half of cells. Significant correlation is observed between skewed X inactivation and smaller gray matter volume in the left insula of the brain, which is involved in social, emotional, and mental processing.
Clinical genetics
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Females who carry an X-linked recessive disorder may display signs and symptoms of an X-linked disorder. This is most commonly because, due to X-chromosome inactivation, 50% of the nuclei in their cells contain the active X chromosome with the mutated gene (Figure 5.16B), e.g. female carriers of haemophilia A, with mutations in the factor VIII gene, may show mild coagulation disorders. Much less often, a female may show a phenotype of similar severity to an affected male. This arises because the mutated X chromosome is active in most or all of her cells. This may be either through non-random inactivation, called skewed X-inactivation, or if she only has a single copy of the X chromosome that carries the mutation, as in a patient with Turner's syndrome (45,XO).
Novel CHRDL1 mutation causing X-linked megalocornea in a family with mild anterior segment manifestations in carrier females
Published in Ophthalmic Genetics, 2022
Rocio Arce-Gonzalez, Oscar F. Chacon-Camacho, Alejandro Navas-Perez, María C. Gonzalez-Gonzalez, Alan Martinez-Aguilar, Juan Carlos Zenteno
Mutations in the CHRDL1 gene were identified as responsible of XMC in 2012 (4) and since then, 8 familial and 13 sporadic XMC cases have been clinically described and molecularly characterized (Table 1). To date, 22 distinct CHRDL1 pathogenic variants have been reported in XMC, most of them predicting truncation of the encoded protein, either due to frameshifting or by direct premature stop codon introduction (nonsense variants). CHRDL1 splicing mutations, as the variant identified in the pedigree described here, are infrequently identified in XMC. Previously, a splice-site mutation in intron 4 (IVS4+2T>G c.301+2T>G) was demonstrated in a XMC pedigree reported by Webb et al. (4). Notably, in all available reports XMC manifest exclusively in males while females who were demonstrated to be CHRDL1 mutation carriers through molecular analysis were not reported as suffering from ocular anomalies (4,6–8). A limitation of our report is that no X–inactivation pattern assays were performed to investigate the possibility of skewed X–inactivation as an explanation for the manifesting heterozygous females in this pedigree. Skewed (biased) X–inactivation has been shown to be responsible for clinical manifestations in female carriers of X-linked ocular diseases as blue cone monochromatism (15) and RPGR-associated X-Linked retinitis pigmentosa (16).
X-Linked Tumor Suppressor Genes Act as Presumed Contributors in the Sex Chromosome-Autosome Crosstalk in Cancers
Published in Cancer Investigation, 2022
Bhanupriya Dhabhai, Amit Sharma, Jarek Maciaczyk, Tikam Chand Dakal
Combining our current data (majority of X-linked TSGs being associated with breast cancer), with the known facts, (a) a higher predisposition to breast cancer in 47 XXY males (compared to 46 XY males) (16), (b) skewed X inactivation as a predisposing factor (17) as well as loss of heterozygosity (LOH) of X-linked genes in the breast cancer (18), the significance of X-linked genes in sex-biased cancers (e.g. breast cancer) can be anticipated. Considering that loss (XO, Turner syndrome) or gain (XXY , Klinefelter syndrome) of the X chromosome may also impact the dosage effect of X-linked genes, one study suggests that absence of the X chromosome may play a role in skin neoplasms, CNS tumors, colon and rectal cancers, though the breast cancer risk appears to be low compared to the general population (19). Similarly, an increased risk of solid tumors has been discussed in Turner syndrome, whereas the risk appeared to be lower in individuals with Klinefelter syndrome (20). Of note, the complete chromosomal loss or gain of X chromosome may itself trigger cancer-causing pathways, potentially due to the autosomal-sex chromosome crosstalk that we have proposed here, however, it is difficult to determine the relative contribution of the X-linked TSG alone in this scenario.
Ocular gene therapy for choroideremia: clinical trials and future perspectives
Published in Expert Review of Ophthalmology, 2018
Kanmin Xue, Robert E. MacLaren
Interestingly, while diffuse fine pattern RPE mottling is usually seen in female CHM carriers due to random X-inactivation, it is generally minimally progressive and not associated with any subjective visual deficit, although a small reduction in macular sensitivity is detectable through microperimetry [26]. The implication is that if gene therapy could achieve approximately 50% diffuse transduction of the RPE monolayer, clinical disease progression may be halted. Occasionally, however, female choroideremia carriers could be affected by patches of retinal degeneration, which expand gradually, thus becoming locally reminiscent of the male disease phenotype. These cases are thought to result from skewed X-inactivation during early retinal development. It could be inferred that if the gene therapy vector transduced the RPE cells non-uniformly, patchy disease progression may still occur. Therefore, both the proportion and distribution of target cell transduction during retinal gene therapy could ultimately influence the clinical efficacy of the treatment. This must be taken into account when interpreting the anatomical outcomes of choroideremia gene therapy.