L11 Numerical Abnormalities of Chromosomes PDF

Cytogenetic Disorder & Numerical Abnormalities Dr. Preetha J Shetty March 4, 2024 www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives Describe aneuploidy and polyploidy and explain their clinical significance Define the following and explain their clinical significance: Somatic mosaicism; Gonadal...

Cytogenetic Disorder & Numerical Abnormalities Dr. Preetha J Shetty March 4, 2024 www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives Describe aneuploidy and polyploidy and explain their clinical significance Define the following and explain their clinical significance: Somatic mosaicism; Gonadal mosaicism Describe the cytogenetic abnormality and salient clinical manifestations of: Down syndrome Patau syndrome Edward syndrome Turner syndrome Kleinfelter syndrome Chromosomal disorder Cytogenetic abnormalities fall into two broad categories: 1. Numerical abnormality 2. Structural abnormality Numerical abnormalities include – Polyploidy: when the chromosome complement is the exact multiple of the haploid number (23) e.g. triploidy condition – Aneuploidy: A chromosome complement that is not an exact multiple of the haploid number (23) e.g. Down syndrome, Turner syndrome Polyploidy Polyploidy can take two forms in humans: a. Triploidy (three sets of chromosomes), and b. Tetraploidy (four sets of chromosomes). Triploidy (3n = 69) occurs in about 1% of conceptuses and as many as 20% of spontaneous abortions with a chromosomal abnormality. Few triploids survive to term, and those that do usually have a quick demise. Diploid/triploid mosaics have had a longer survival. Autosomal Aneuploidy Autosomal aneuploidy refers to abnormalities that involve the autosomes. The incidence of autosomal aneuploidy in newborns is estimated to be 0.2%. Many autosomal aneuploidies are incompatible with fetal survival and, therefore, have much higher incidences (approximately 27–30%) in spontaneous abortuses. Sex Chromosomes Aneuploidy Sex chromosome aneuploidy are one of the most common types of chromosomal aneuploidy, with a frequency of 1 in 500 live births. Abnormalities of sex chromosomes have less severe clinical manifestations and are more compatible with life as compared to autosomal disorders. Reasons for this include inactivation of all additional X chromosomes and the small number of genes on the Y chromosome. Causes of aneuploidy 1. Nondisjunction in Mitosis Nondisjunction of the early zygote during mitotic division produces mosaicism: the presence in an individual of two or more genetically different cell populations. In this type of nondisjunction (which may also occur during the second meiotic division), the two chromatids of a duplicated chromosome fail to divide. Mosaic individuals manifest phenotypic abnormalities that are intermediate between those associated with the two cell populations; eg, 45,X/46,XX is mosaic a Turner syndrome karyotype, and the individual's appearance will be somewhere between that of a normal female and those of an individual with classic Turner syndrome (45,XO). Causes of aneuploidy 2. Anaphase lag: one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus. The result is one normal cell and one cell with monosomy. Two anaphase spindles from the control (lower) and Kif2b-depleted (upper) cells. See how the upper spindle contains chromosomes. two lagging Microtubules are shown in red, chromosomes in blue, and the kinetochore marker is in green. Causes of aneuploidy 3. Nondisjunction In meiosis A homologous pair of chromosomes fails to disjoin at the first meiotic division, or the two chromatids fail to separate either at the second meiotic division or in somatic cell divisions, resulting in two aneuploid cells Causes of aneuploidy An aneuploid gamete + a normal gamete an aneuploid zygote (with either 3 of the involved chromosomes (trisomy) or only 1 (monosomy). Trisomy and monosomy of the sex chromosomes are generally compatible with life. Autosomal monosomy is associated with a profound loss of genetic material and is usually lethal. A few autosomal trisomies (21, 13, and 18) may be compatible with survival but are associated with severe abnormalities Trisomy 21: Down's syndrome Most common chromosomal disorder (1 in 700 live births) and a major cause of mental retardation Advanced maternal age is grave risk factor. Incidence: 1 in 25 live births to mothers over 45 95% have three separate 21's; Advanced maternal age is only a risk factor for the first group -meiotic nondisjuntion 4% have a translocation -Robertsonian t (14;21or 22;21) One parent (usually the mother) is a carrier of the translocation 1% are mosaics Mitotic non-disjunction of chromosome 21 during early embryogenesis Symptoms are variable and milder- depending on the proportion of abnormal cells Trisomy 21: Down's syndrome-types Three types of Down syndrome are recognized: Nondisjunction Down Syndrome Accounts for 95% of the cases. Associated with increasing maternal age (over age 35 years). The child has an extra 21 chromosome (47,XX,+21 or 47,XY,+21); the parents have normal karyotypes. Translocation Down Syndrome 5% of the cases- due to inheritance of a balanced translocation from one of the parents commonly a 14,21 translocation more rarely a 21,22 translocation. One parent carries the abnormal chromosome. The infant with Down syndrome has 46 chromosomes, one of which has the genetic material of both chromosomes 14 and 21. Translocation Down syndrome is not associated with increased maternal age but is familial. Mosaic Down Syndrome Very rare type of Down syndrome, Nondisjunction occurs during an early mitotic division in the developing embryo. Only one of two cell lines in the body shows trisomy for chromosome 21. Karyotype showing trisomy 21- Down Syndrome Edwards' Syndrome (Trisomy 18) Trisomy 18 was independently described by Edwards et al and Smith et al in 1960 Trisomy 18 (47,XX/XY,+18) is rare. 1 in 6,0008,000 live births. 80% of cases occur in females. It produces severe defects, and few children survive beyond 1 year of age. Clinically, failure to thrive severe mental retardation characteristic physical abnormalities such as rocker-bottom feet and clenched hands with overlapping fingers. rocker-bottom foot with prominent calcaneus Infant with Edwards syndrome. Note microphthalmia, micrognathia/retrognathia, microstomia, low set/malformed ears, short sternum, and abnormal clenched fingers clenched hand with the index finger overriding the middle finger and the fifth finger overriding the fourth fingers. Patau's Syndrome (Trisomy 13) Trisomy 13 (47,XX/XY,+13) is also rare. Most affected infants die soon after birth. Trisomy 13 is characterized by abnormal development of the forebrain midline facial structures (cleft lip, cleft palate, nasal defects, single central eye [cyclops]. Cytogenetic disorders of the sex chromosomes Far more common than those related to autosomal aberrations Imbalances (excess or loss) of sex chromosomes are better tolerated Peculiarities of the sex chromosomes (1) lyonization or inactivation of all but one X chromosome by Xist 1. Only one X is active, the inactive one is hyperpyknotic 2. Inactivation is random among the cells of the blastocyst (16th day of the embryonic life) 3. The same chromosome remains inactive in all cells derived from each of the precursor (2) Amount of genetic material carried by the Y chromosome is modest (1) A single Y chromosome determines the male sex (Sry, MSY) Features that are common to all sex chromosome disorders Cause subtle, chronic problems relating to sexual development and fertility. Often difficult to diagnose at birth, and may be first recognized at the time of puberty. Higher the number of X chromosomes, in both male and female, the greater the likelihood of mental retardation. Eg: Turner syndrome: 45, XO- Female hypogonadism Kleinfelter syndrome: 47 XXY- Male hypogonadism Turner Syndrome Turner syndrome occurs in 1:2500 live female births. It is caused by nondisjunction of the X chromosome in either parent of an affected female, leading to absence of one X chromosome (45,XO). About half of patients with Turner syndrome show mosaicism (45,X/46,XX) owing to nondisjunction occurring in a post zygotic mitotic division. The diagnosis may be established by absence of Barr bodies in the buccal smear of a female and by karyotypic analysis. KLINEFELTER’S SYNDROME Have 47 chromosomes (XXY) & a sex chromatin Barr body or 48(XXXY); more the number of X more the chances of mental impairment Cause: Nondisjunction of XX homologue Found only in males, detected at puberty Incidence ---1 in 500 males S/S Sterility, testicular atrophy, hyalinization of seminiferous tubules, gynecomastia. More examples XXX Syndrome (Superfemale) The presence of a third X chromosome in a female causes the triple X disorder. Most patients are normal. A few show mental retardation, menstrual problems, and decreased fertility. XYY Syndrome The presence of an extra Y chromosome in a male causes XYY syndrome. Most patients appear normal. A minority may show aggressive behavior and mild mental retardation. The incidence is 1:1000 male births. Fragile X Syndrome This syndrome is associated with mental retardation in 80% of males who carry the abnormal chromosome but only 30% of females (perhaps due to preferential inactivation of the abnormal X chromosome). The abnormality consists of an unusually large number of repeat nucleotide triplets close to the tip of the long arm of the X chromosome (Xq27). Growth abnormalities may occur in addition to severe retardation. The frequency may be as high as 1:1000 in males and 1:2000 in females Mosaicism Mosaicism is the presence of two or more genetically different cell lines in an individual, all derived from a single zygote Mosaicism can be for chromosomal or single gene disorders Mosaicism may affect either somatic or germline tissues Somatic Mosaicism can result in a range of abnormality depending on the amount and distribution of normal cells (e.g. mosaic Down syndrome, non-inherited cancers) Gonadal (germline) mosaicism affects the germline tissues, explains the increased risk of recurrence in disorders due to new dominant mutations Mosaicism Mosaicism affecting the sex chromosomes is relatively more common. Early error in mitosis- variant form of Turner syndrome- 45,X / 47,XXX mosaic an error at a later stage may result in 45,X / 46,XX / 47,XXX Autosomal mosaicism appears to be much less common early mitotic division affecting the autosomes usually leads to a nonviable mosaic with autosomal monosomy. Rarely, the loss of a nonviable cell line in embryogenesis is tolerated, yielding a mosaic (e.g., 46,XY/47,XY,+21). Germline Mosaicism Embryo No previous family history of this disorder All or part of a parent’s germ line is affected by a disease mutation, but the somatic cells are not