Karyotyping and Sex-Linked Disorders PDF

36 Karyotyping and X-linked disorders **ILOs** ***By the end of this lecture, students will be able to*** 1. Determine characteristics of X-linked disorders. 2. Calculate the recurrence risk of monogenic X linked genetic disorders using Punnett square. 3. Interpret pedigrees with X-link...

36 Karyotyping and X-linked disorders **ILOs** ***By the end of this lecture, students will be able to*** 1. Determine characteristics of X-linked disorders. 2. Calculate the recurrence risk of monogenic X linked genetic disorders using Punnett square. 3. Interpret pedigrees with X-linked recessive and dominant diseases. 4. Correlate inherited X linked disorders with X-linked recessive and dominant modes of inheritance. 5. Interpret karyogram and karyotype formulae. **Sex-Linked Inheritance** Sex-linked inheritance refers to the pattern of inheritance shown by genes that are located on either of the sex chromosomes. Genes carried on the X chromosome are referred to as being X-linked, and those carried on the Y chromosome are referred to as exhibiting Y-linked inheritance. **X-Linked Recessive Inheritance** - Manifests mainly in males. A male with a mutant allele on his single X chromosome is said to be **homozygous** for that allele. - Females may be affected if the father is affected and the mother is an asymptomatic carrier. **Genetic risk X-Linked Recessive Inheritance** - **For a male affected with X-linked recessive disease** has children with a normal female, then all of his daughters will be **obligate carriers** but none of his sons will be affected "A male cannot transmit an X-linked trait to his son". - Obligate carriers may transmit the disease to their sons in the future (**diagonal pattern** of transmission due to affected male relatives on maternal side) (Figure 1). - **For a carrier female of an X-linked recessive disorder** having children with a normal male, each son has a 50% chance of being affected and each daughter has a 50% chance of being a carrier (Figure 2). - Some X-linked disorders are not compatible with survival to reproductive age and are not, therefore, transmitted by affected males. **Duchenne muscular dystrophy** is the commonest muscular dystrophy and is a severe disease. Affected males often die in their late teenage years or early 20s. Because affected boys do not usually survive to reproduce, the disease is transmitted by healthy female carriers, or may arise as a new mutation.  ### **X-Linked Dominant Inheritance** - Uncommon, - Manifest in the heterozygous female as well as in the male who has the mutant allele on his single X chromosome. - **An affected female** transmit the trait to both her daughters and sons equally with a 50% chance of being affected regardless the sex (Figure 3 & 4A). - **An affected male transmits** the trait to all his daughters but to none of his sons (Figure 3 & 4B). - Therefore, in families with an X-linked dominant disorder there is an excess of affected females and direct male-to-male transmission cannot occur. - Females are often less affected than males due to X chromosome inactivation. **Examples of X-Linked dominant Inheritance** **X-linked hypophosphatemia**, (**Vitamin D-resistant rickets)**: Rickets can be due to a dietary deficiency of vitamin D, but in vitamin D--resistant rickets the disorder occurs even when there is an adequate dietary intake of vitamin D. In the X-linked dominant form of vitamin D-resistant rickets, both males and females are affected with short stature due to short and often bowed long bones, although the females usually have less severe skeletal changes than the males. **Y-Linked Inheritance** Only males are affected. ### ### **KARYOTYPING** **Karyotyping** is the process of pairing and ordering all the chromosomes of an organism, thus providing a genome-wide snapshot of an individual\'s chromosomes. Karyotyping detects gross genetic changes either numerical or structural anomalies involving several megabases or more of DNA. A variety of tissue types can be used as a source of these cells. For cancer diagnoses, typical specimens include tumor biopsies or bone marrow samples. For other diagnoses, karyotypes are often generated from peripheral blood specimens or a skin biopsy. For prenatal diagnosis, amniotic fluid or chorionic villus specimens are used as the source of cells. **Preparing Karyotypes from Mitotic Cells** ------------------------------------------- Karyotypes are prepared from mitotic cells that have been arrested in the [metaphase](https://www.nature.com/scitable/topicpage/Mitosis-Cell-Division-and-Asexual-Reproduction-205) or prometaphase portion of the cell cycle, when chromosomes assume their most [condensed conformations](https://www.nature.com/scitable/topicpage/DNA-Packaging-Nucleosomes-and-Chromatin-310). Without any treatment, structural details of chromosomes are difficult to detect under a light microscope. Thus, to make analysis more effective and efficient, cytologists have developed stains that bind with DNA and generate characteristic banding patterns for different chromosomes. The most frequently used techniques are G- (giemsa), Q- (quinacrine) and R- (reverse) banding. The various banding techniques produce light and dark bands on the chromosomes that are specific to each chromosome and that hence permit unequivocal identification of the individual chromosomes. In general, heterochromatic regions, which tend to be AT-rich DNA and relatively gene-poor, stain more darkly in G-banding. In contrast, less condensed chromatin which tends to be GC-rich and more transcriptionally active appear as light bands in G-banding. According to international consensus, 20--25 should be fully analyzed in order to produce a reliable diagnosis. **The karyotype formula** An international cytogenetic nomenclature (ISCN: International System of Cytogenetic Nomenclature) provides an exact description of all numerical and structural aberrations in a karyotype formula. The karyotype formula first states the number of chromosomes, followed by the statement of gender chromosomes. Hence, the normal female karyotype is 46,XX, while the normal male karyotype is 46,XY. The karyotype formula denotes: - Gain of a chromosome with a "**+**" e.g. 47,XX,+8: trisomy of chromosome 8 - Loss of a chromosome with "-" e.g. 45,XY,-7, describes monosomy of chromosome 7. - "t" for translocation e.g. t(8;21)(q22;q22) means that a breakpoint has occurred in band q22 of chromosome 8, another one in band q22 of chromosome 21, and that translocation of the fractions has taken place between the chromosomes. - "inv" for inversion: inv(16)(p13q22): i.e. breaks took place in the chromosome bands p13 and q22 of the same chromosome 16, and the segment between both breakpoints was inverted by 180°. - del(5)(q13q31), i.e. the breaks took place in the bands q13 and q31 of the same chromosome 5, and the region between q13 and q31 has been lost.  ### ### ### ### ###