1. Sex Chromosomes and Abnormalities

2. Sex chromosomes At the cellular level the sex of an individual is determined genetically by the sex chromosomes. X and Y -> male X and X -> female

6. Dosage Compensation Human females inherit two copies of every gene on the X chromosome, whereas males inherit only one But for the hundreds of other genes on the X, are males at a disadvantage in the amount of gene product their cells produce? The answer is no, because females have only a single active X chromosome in each cell.

8. Mary Lyon ve Liane Russell (1961) In a given cell, which of a female's X chromosomes becomes inactivated and converted into a Barr body is a matter of chance. After inactivation has occurred, all the descendants of that cell will have the same chromosome inactivated. Thus X-chromosome inactivation creates clones with different effective gene content. X inactivation “ Lyon Hypothesis”

9. Barr Body 01 23 Normal male, Turner Normal female, Klinefelter

10. Barr Body

11. Lyon Hypothesis X-chromosome inactivation occurs early in embryonic development.

12. Mechanism of X-chromosome inactivation Inactivation of an X chromosome requires a gene on that chromosome called XIST. XIST encodes a large molecule of RNA XIST RNA accumulates along the X chromosome containing the active XIST gene and proceeds to inactivate all (or almost all) of the hundreds of other genes on that chromosome. Barr bodies are inactive X chromosomes "painted" with XIST RNA.

14. Xist RNA İnaktif X kromozomu

16. Genes on the Y chromosome Y chromosome first seen 1923 Tips of Y chromosome are pseudoautosomal regions PAR1 and PAR2 They make up 5% of the chromosome Contain 63 pseudoautosomal genes that cross over with the X chromosome

17. Genes on the Y Chromosome Y chromosome has 2 pseudoautosomal regions whose genes match genes on the X chromosome And a large central region that does not recombine with the X chromosome This non-recombining region makes up about 95% of the chromosome

18. X and Y are not homologous

20. Cytogenetic Abnormalities of the Sex Chromosomes Sex chromosome abnormalities, like abnormalities of the autosomes, can be either numerical or structural and can be present in all cells or in mosaic form.

21. Cytogenetic Abnormalities of the Sex Chromosomes X and Y chromosome aneuploidy is relatively common, and sex chromosome abnormalities are among the most common of all human genetic disorders, with an overall incidence of about 1 in 400 to 500 births. The phenotypes associated with these chromosomal defects are, in general, less severe than those associated with comparable autosomal disorders.

22. Cytogenetic Abnormalities of the Sex Chromosomes Structural abnormalities of the sex chromosomes are less common; the defect most frequently observed is an isochromosome of the long arm of the X, i(Xq), seen in complete or mosaic form in at least 15% of females with Turner syndrome. Mosaicism is more common for sex chromosome abnormalities than for autosomal abnormalities, and in some patients it is associated with relatively mild expression of the associated phenotype.

23. Klinefelter Syndrome (47,XXY) The phenotype of Klinefelter syndrome, the first human sex chromosome abnormality to be reported The patients are tall and thin and have relatively long legs. They appear physically normal until puberty, when signs of hypogonadism become obvious.

25. Clinical Picture – Undersized penis and testes hypospadias, small phallus or cryptorchidism, – Infertile, – Somewhat feminized physical chracteristics – If desired, the XXY boy can increase male secondary sex characteristics (body hair, reduced breast development, increased muscle development) w/testosterone treatment – language delay, learning disabilities, or behavioral problems

26. Puberty occurs at a normal age, but the testes remain small, and secondary sexual characteristics remain underdeveloped. Gynecomastia is a feature of some patients; because of this, the risk of breast cancer is 20 to 50 times that of 46,XY males. Klinefelter patients are almost always infertile because of the failure of germ cell development, and patients are often identified clinically for the first time because of infertility. The incidence is at least 1 in 1000 male live births

27. Associated endocrine complications include diabetes mellitus, hypothyroidism, and hypoparathyrodism... Lupus erythematosus, Sjogren syndrome, and rheumatoid arthritis, are more common Patients have often; a low serum testosterone level buttestosterone high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.follicle-stimulating hormone luteinizing hormone

28. About 15% of Klinefelter patients have mosaic karyotypes. As a group, such mosaic patients have variable phenotypes; some may have normal testicular development. The most common mosaic karyotype is 46,XY/47,XXY. There are several variants of Klinefelter syndrome, with karyotypes other than 47,XXY, including 48,XXYY, 48,XXXY, and 49,XXXXY. As a rule, the additional X chromosomes cause a correspondingly more severe phenotype, with a greater degree of dysmorphism, more defective sexual development, and more severe mental impairment.

29. 47,XYY Syndrome The 47,XYY chromosome constitution is not associated with an obviously abnormal phenotype, and males with this karyotype cannot be distinguished from normal 46,XY males by any marked physical or behavioral features.

30. Trisomy X (47,XXX) Trisomy X females, although somewhat above average in stature, are not abnormal phenotypically. XXX females develop pubertal changes at an appropriate age, and they are usually fertile although with a somewhat increased risk of chromosomally abnormal offspring. There is a significant deficit in performance on IQ tests, and about 70% of the patients have some learning problems.

31. Turner Syndrome (45,X and Variants) Turner syndrome is much less common than other sex chromosome aneuploidies. The incidence of the Turner syndrome phenotype is approximately 1 in 4000 female live births, although much higher numbers have been reported in some surveys.

33. Turner Syndrome (45,X and Variants) Turner syndrome can often be identified at birth or before puberty by their distinctive phenotypic features At birth, infants with this syndrome often have edema of the dorsum of the foot. short stature, gonadal dysgenesis (usually streak gonads reflecting a failure of ovarian maintenance) characteristic unusual facies webbed neck low posterior hairline broad chest with widely spaced nipples elevated frequency of renal and cardiovascular anomalies.

34. Turner Syndrome (45,X and Variants) Lymphedema may be present in fetal life, causing cystic hygroma (visible by ultrasonography), which is the cause of the neck webbing seen postnatally. The diagnosis should also be considered in the teenage years for girls with primary or secondary amenorrhea, especially if they are of short stature.

35. The most frequent chromosome constitution in Turner syndrome is 45,X (sometimes written incorrectly as 45,XO), with no second sex chromosome. However, about 50% of cases have other karyotypes. About one quarter of Turner syndrome cases involve mosaic karyotypes, in which only a proportion of cells are 45,X.

36. The most common karyotypes and their approximate relative prevalences are as follows: 46,X,i(Xq) 15% 45,X/46,XX mosaics 15% 45,X/46,X,i(Xq) mosaics about 5% 45,X, other X abnormality about 5% Other 45,X/? mosaics about 5%

37. The chromosome constitution is clinically significant. For example, patients with i(Xq) are similar to classic 45,X patients, whereas patients with a deletion of Xp have short stature and congenital malformations, and those with a deletion of Xq often have only gonadal dysfunction.