Medical Biology and Genetics (Chromosomal Abnormalities) PDF

MEDICAL BIOLOGY AND GENETICS Chromosomal Abnormalities Dr. Ceyhan Ceran Serdar – 2024-2025 Reference Books  Learning Outcomes 1. Understand the genetic basis of numerical and structural chromosome syndromes and learn how chromosomal anomalies occur. 2. Recogni...

MEDICAL BIOLOGY AND GENETICS Chromosomal Abnormalities Dr. Ceyhan Ceran Serdar – 2024-2025 Reference Books  Learning Outcomes 1. Understand the genetic basis of numerical and structural chromosome syndromes and learn how chromosomal anomalies occur. 2. Recognize the clinical features of different numerical and structural chromosome syndromes and learn about diagnostic methods and management strategies for these syndromes. 3. Recognize common syndromes and disorders caused by chromosomal abnormalities, such as Down syndrome, Turner syndrome, and Klinefelter syndrome, and evaluate their effects, diagnosis, and treatment options. Chromosomal Abnormalities  Terminologies Mechanisms of Chromosomal Abnormalities Aneuploidy: A condition where there is an abnormal number of chromosomes in a cell. Trisomy 21 (Down Syndrome): A genetic disorder caused by the presence of an extra copy of chromosome 21. Trisomy 18 (Edwards Syndrome): A genetic disorder caused by the presence of an extra copy of chromosome 18. Trisomy 13 (Patau Syndrome): A genetic disorder caused by the presence of an extra copy of chromosome 13. Uniparental Disomy: A condition in which a person receives two copies of a chromosome from one parent instead of one copy from each parent. Genomic Disorders: Microdeletion and Microduplication Syndromes: Genetic disorders caused by deletions or duplications of small pieces of a chromosome. Idiopathic Chromosomal Abnormalities: Chromosomal abnormalities with an unknown cause. Segregation of Familial Abnormalities: The passing down of chromosomal abnormalities from one generation to the next within a family. Genomic Imprinting Disorders: Disorders caused by the differential expression of genes depending on whether they are inherited from the mother or the father.  Glossary Hydrops: Swelling of the baby's entire body due to heart failure Micrognathia: Shortness of the lower jawbone. Microcephaly: The head is smaller than normal Omphalocele: The protrusion of the baby's intestines through an opening in the abdominal wall Polyhydramnios: Excess amniotic fluid  Mechanisms of Chromosomal Abnormalities CHROMOSOMAL ABNORMALITIES NUMERICAL ABNORMALITIES STRUCTURAL ABNORMALITIES Polyploidy Deletion Aneuploidy Duplication Sex chromosome Inversion aneuploidy Insertion Autosomal aneuploidy Ring chromosome Isochromosome Mosaicism it covers all of them Translocations Robertsonian Reciprocal THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 7 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Structural Chromosomal Abnormalities Structural Abnormalities Structural Abnormalities Involving Single Chromosome Involving Two Chromosomes. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 7 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. Structural chromosomal abnormalities Figure 5-11 Structural rearrangements of chromosomes, described in the text. A, Terminal and interstitial deletions, each generating an acentric fragment that is typically lost. B, Duplication of a chromosomal segment, leading to partial trisomy. C, Ring chromosome with two acentric fragments. D, Generation of an isochromosome for the long arm of a chromosome. E, Robertsonian translocation between two acrocentric chromosomes, frequently leading to a pseudodicentric chromosome. Robertsonian translocations are nonreciprocal, and the short arms of the acrocentrics are lost. F, Translocation between two chromosomes, with reciprocal exchange of the translocated segments. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 5 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Poliploidy Human sex cells (gametes) contain 23 chromosomes. This number is referred to as haploid (n). A multiple of the haploid chromosome number is called "euploid". Haploid: n = 23 Diploid: 2n = 46 Triploid: 3n = 69 Tetraploid: 4n = 92 Polyploidy Autopolyploidy: An increase in the number of chromosome sets within a species. Allopolyploidy: An increase in chromosome number due to hybridization between closely related species. Mechanisms of Polyploidy Anaphase Lag: Failure of chromosomes to separate properly during anaphase. Endoreduplication: Duplication of chromosomes without nuclear division. Failure of cytokinesis: Failure of the cell to divide after nuclear division. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 7 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Triploidy Triploidy is a chromosomal abnormality characterized by the presence of an extra set of chromosomes, resulting in three sets of chromosomes (69 for humans). It is reported to be observed in approximately 3% of all pregnancies. Most triploidy cases result in spontaneous abortion, and live births are lost early in the postnatal period Triploidy typically results from dispermy (fertilization of an egg by two sperm) or errors in meiosis leading to an egg with an extra set of chromosomes (diploid instead of haploid).  Aneuploidy Fertilization involving a gamete with an extra copy of one chromosome  results in a zygote with three copies of that chromosome  this is called trisomy,  indicated as 2n + 1 The converse case, involving a gamete missing a copy of one chromosome,  results in a zygote with only one copy of the chromosome  this is called monosomy  indicated with 2n – 1 THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 5 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. Jeff Hardin, James P. Lodolce, Becker's World Of The Cell 10th Ed. Global Ed. Chapter: 25. Pearson Education, Ltd, 2022ublishing as Pearson Benjamin Cummings THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 5 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Aneuploidy Aneuploidy refers to a condition where there is an abnormal number of chromosomes in a cell. This means there are either extra chromosomes or missing chromosomes compared to the normal number. Note: It's important to note that this is different from polyploidy, where there are complete extra sets of chromosomes. Examples of aneuploidy: Trisomy: Having an extra copy of a chromosome (e.g., Trisomy 21, Down syndrome). Monosomy: Having only one copy of a chromosome instead of two. Partial Aneuploidy: If only a part of a chromosome is extra or missing, it's called a partial aneuploidy. Mosaic Aneuploidy: This occurs when some cells in the body have the correct number of chromosomes, while others have an abnormal number. Incidence in Newborns: Approximately 20% of newborns have autosomal aneuploidy. However, due to the severity of many aneuploidies, many affected pregnancies end in miscarriage. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 7 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Aneuploidy Because they have a poorer genetic content, the most common aneuploidies seen in live births are Trisomy 21 (Down syndrome): The most common autosomal trisomy. Trisomy 18 (Edwards syndrome): Often leads to severe developmental problems and early death. Trisomy 13 (Patau syndrome): Similar to Trisomy 18, with severe developmental abnormalities. Although other trisomies occur with similar frequency during pregnancy, they lead to devastating imbalances incompatible with life, resulting in very low live birth rates. Mechanisms of Aneuploidy: Non-disjunction: Failure of chromosomes to separate properly during cell division. Anaphase lagging: When a chromosome lags behind during cell division and is not included in either daughter cell. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Mechanisms of Chromosomal Abnormalities Major chromosomal and genomic mechanisms underlying genetic imbalances involving whole chromosomes or chromosomal regions can be categorized into 5 groups: 1. Disorders due to abnormal chromosome segregation: These occur when chromosomes fail to separate correctly during cell division. 2. Recurrent chromosomal syndromes involving deletions or duplications in genomic hotspots: These are syndromes caused by repeated deletions or duplications in specific regions of the genome. 3. Idiopathic chromosomal abnormalities: These are chromosomal abnormalities with an unknown cause that arise spontaneously. 4. Disorders due to unbalanced familial chromosomal abnormalities: These are inherited chromosomal abnormalities that cause a genetic imbalance in the offspring. 5. Chromosomal and genomic events that reveal genomic imprinting regions: These are events that expose regions of the genome where genes are expressed differently depending on whether they are inherited from the mother or the father. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Types of Abnormal Chromosome Segregation Errors in Meiosis Leading to Aneuploidy Nondisjunction in Meiosis I: This occurs when homologous chromosomes fail to separate properly during the first meiotic division, resulting in gametes with an abnormal number of chromosomes. Premature separation of sister chromatids in Meiosis I: Often associated with advanced maternal age, this occurs when sister chromatids separate prematurely during the first meiotic division. Nondisjunction in Meiosis II: Failure of sister chromatids to separate properly during the second meiotic division. Anaphase Lagging: When a chromosome fails to move towards the pole during anaphase, leading to an unequal distribution of chromosomes in the daughter cells. Cytokinesis Failure: This occurs when the cytoplasm of a cell fails to divide after nuclear division, resulting in a single cell with two nuclei. These errors in meiosis can lead to aneuploidy, a condition where a cell has an abnormal number of chromosomes. This is a common cause of genetic disorders such as Down syndrome, Turner syndrome, and Klinefelter syndrome. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Segregation Errors in Meiosis I and II Occasionally an error in segregation called nondisjunction occurs This produces cells  that have an extra chromosome  or are missing one,  a condition called aneuploidy If aneuploid gametes fuse with normal gametes,  defective embryos are produced  that usually die before birth Jeff Hardin, James P. Lodolce, Becker's World Of The Cell 10th Ed. Global Ed. Chapter: 25. Pearson Education, Ltd, 2022ublishing as Pearson Benjamin Cummings Nondisjunction in Meiosis I and Meiosis II Separation of chromatids earlier than expected due to high maternal age Segregation in Robertsonian Translocations Figure 5-12 A, Diagram illustrating a balanced translocation between two chromosomes, involving a reciprocal exchange between the distal long arms of chromosomes A and B. B, Formation of a quadrivalent in meiosis is necessary to align the homologous segments of the two derivative chromosomes and their normal homologues. C, Patterns of segregation in a carrier of the translocation, leading to either balanced or unbalanced gametes, shown at the bottom. Adjacent-1 segregation (in red, top chromosomes to one gamete, bottom chromosomes to the other) leads only to unbalanced gametes. Adjacent-2 segregation (in green, left chromosomes to one gamete, right chromosomes to the other) also leads only to unbalanced gametes. Only alternate segregation (in gray, upper left/lower right chromosomes to one gamete, lower left/upper right to the other) can lead to balanced gametes. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 5 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  INVERSIONS An anomaly called inversion occurs when the segment between two breaks in a chromosome rotates 180° around itself and fuses again. There are 2 types: Pericentric Inversion Paracentric Inversion Paracentric – Pericentric Inversion Figure 5-13 Crossing over within inversion loops formed at meiosis I in carriers of a chromosome with segment B-C inverted (order A-C-B-D, instead of the normal order A-B-C-D). A, Paracentric inversion. Gametes formed after the second meiosis usually contain either a normal (A-B-C-D) or a balanced (A-C-B-D) copy of the chromosome because the acentric and dicentric products of the crossover are inviable. B, Pericentric inversion. Gametes formed after the second meiosis may be balanced (normal or inverted) or unbalanced. Unbalanced gametes contain a copy of the chromosome with a duplication or a deficiency of the material flanking the inverted segment (A-B-C-A or D-B-C-D). THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 5 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. Trisomic Syndromes Most Common Trisomic Syndromes THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. DOWN SENDROME (Trisomy 21) (Trisomy-G) DOWN SENDROME (Trisomy 21) (Trisomy-G) - The phenotype, described by John Langdon Down in 1866, is the first chromosomal abnormality described in man. - Incidence in the population is ~1/700 – 1/850. - Among women aged 35 years and older, the incidence of trisomy 21 is much higher. - Only ~20-25% of pregnancies with trisomy 21 can survive after birth. - Those least likely to survive are those with congenital heart disease. About 1/4 of babies with Down syndrome who are born alive with heart disease die before their first birthday. Figure 6-2 Phenotype of Down syndrome. A, Young infant. The nasal bridge is flat; ears are low-set and have a characteristic folded appearance; the eyes show characteristic epicanthal folds and upslanting palpebral fissures; the mouth is open, showing a protruding tongue. B, Brushfield spots around the margin of the iris (arrow). THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  DOWN SENDROME (Trisomy 21) (Trisomy-G) Figure 6-1 Maternal age dependence on incidence of trisomy 21 at birth and at time of amniocentesis. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Down Syndrome When a zygote with three copies of chromosome 21 is produced,  the resulting embryo can develop fully However, the child will exhibit a series of developmental abnormalities,  together called Down syndrome (trisomy 21) Down syndrome was described by Langdon Down in 1866. Individuals with Down syndrome have  a readily recognizable facial appearance  flattening of the facial profile,  small nose,  epicanthal folds, and Figure 5-40. Down syndrome.  Brushfield spots (focal areas of dysplasia on the iris). (a) Typical facial features. (b) Eye showing Brushfield  notably short fifth fingers, spots (small light colored spots within the iris due to  a wide gap between the first and second toes, focal dysplasia of the connective tissue). (c) Single  and single transverse palmar creases transverse palmar (simian) crease. (d) Wide gap between first and second toes. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Down Syndrome Down syndrome is estimated to occur at 1 in 800 live births. The incidence of trisomy 21 is much higher among women aged 35 and older. Only ~ 20-25% of trisomy 21 pregnancies survive after birth. Those who are least likely to survive are those with congenital heart disease. About of babies with Down's syndrome who are born alive with heart disease die before their first birthday. The vast majority (95%) of individuals with Down syndrome  have whole chromosome aneuploidy (trisomy 21) as the etiology. Another 4%  have a variety of translocations,  most importantly a 14:21 Robertsonian translocation. Approximately 1% of individuals with Down syndrome  have mosaicism THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Risk of DOWN SYNDROME While the age of the mother is a major risk factor, the risk depends on the karyotypes of both parents. Diagnosis of Down Syndrome in the prenatal period can be made with Karyotype analysis Chromosomal microarray analysis Genome-wide sequencing from cells in chorionic villi or amniotic fluid Non-Invasive Prenatal Screening of Cell-Free Fetal DNA in Maternal Plasma (NIPS) Before invasive Prenatal Diagnosis is offered, the balance between the risk of the fetus having Down syndrome and the risk of chorionic villus biopsy resulting in fetal loss should be evaluated. Although the risk of a fetus with Down syndrome increases with maternal age, 50% of mothers of babies with Down syndrome are younger than 35 years of age, as the birth rate of young mothers is higher. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  DOWN SENDROME (Trisomy 21) (Trisomy-G) There is a high degree of variability in the phenotype of individuals with Down syndrome: The most prominent finding after birth is hypotonia (abnormally low muscle tone). Characteristic dysmorphic facial features include: Brachycephaly: Short, broad head Flat occiput: Flat back of the head Depressed nasal bridge: Flattened area between the eyes Low-set and mal-rotated ears Hypertelorism: Wide-set eyes Epicanthal folds: Folds of skin at the inner corner of the eyes Brushfield spots: White spots on the iris Macroglossia: Enlarged tongue Simian crease: A single crease across the palm of the hand Fifth finger clinodactyly: Curved fifth finger Sandals gap: Space between the first and second toes Planar dermatoglyphics: Abnormal skin creases on the soles of the feet" THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. DOWN SENDROME (Trisomy 21) (Trisomy-G)  DOWN SENDROME (Trisomy 21) (Trisomy-G) Mental retardation (mental retardation) is observed. IQ is between 30-60. Congenital heart defects are present. Duodenal atresia (since there is a lack of intestinal formation, transmission is reduced due to intestinal stenosis) and tracheoesophageal fistula are common. There is a 15-fold increase in the risk of leukemia. Premature dementia associated with the typical neurological manifestations of Alzheimer's disease (cortical atrophy, ventricular dilatation, neurofibrillary nodes) is observed in almost all patients with Down syndrome in the general population, several years before the onset of Alzheimer's. Despite all this, they can communicate and lead their lives on their own. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  DOWN SENDROME (Trisomy 21) (Trisomy-G) - A genetic report is legally required for them to be able to study in private schools and for the individuals who take care of them to receive financial assistance. - Clinical diagnosis is easy. - Karyotyping is necessary to confirm the diagnosis and for genetic support. - Determining the abnormal karyotype responsible for Down syndrome usually has little effect on the patient's phenotype. However, it is necessary to determine the risk of recurrence in the family. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Chromosomes in DOWN SYNDROME Trisomy 21 95% of patients have an extra copy of chromosome 21. This trisomy is due to the nondisjunction of chromosome 21 pairs. Meiotic error is observed in ~90% of maternal meiosis (mostly in meiosis I). in ~10% of paternal meiosis (mostly in meiosis II). Trisomy 21 is a sporadic event and has a low risk of recurrence. Robertsonian Translocation In ~4% of patients, there are 46 chromosomes formed by Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (14 or 21). Ex: 46, XX, rob (14; 21), +21 46, XX, rob (14; 21), +21 A person who is a Robertsonian translocation carrier has 45 chromosomes. One chromosome 14 and one chromosome 21 are missing. These missing chromosomes have been replaced by the translocation chromosome. Such carriers have a risk of having a child with the translocation type Down syndrome. There is a high risk of recurrence. Before proper genetic counseling is provided, it is important for parents and other relatives to have a karyotype analysis done. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Robertsonian (14; 21) Carrier Figure 6-3 Chromosomes of gametes that theoretically can be produced by a carrier of a Robertsonian translocation, rob(14;21). A, Normal and balanced complements. B, Unbalanced, one product with both the translocation chromosome and the normal chromosome 21, and the reciprocal product with chromosome 14 only. C, Unbalanced, one product with both the translocation chromosome and chromosome 14, and the reciprocal product with chromosome 21 only. Theoretically, there are six possible types of gamete, but three of these appear unable to lead to viable offspring. Only the three shaded gametes at the left can lead to viable offspring. Theoretically, the three types of gametes will be produced in equal numbers, and thus the theoretical risk for a Down syndrome child should be 1 in 3. However, extensive population studies have shown that unbalanced chromosome complements appear in only approximately 10% to 15% of the progeny of carrier mothers and in only a few percent of the progeny of carrier fathers who have translocations involving chromosome 21. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. 41 42 43 44 45 46 47 48 49 50 51 52  Chromosomes in DOWN SYNDROME 21q21q Translocation It is observed in very few patients with Down syndrome. It is estimated that it originated from an isochromosome. The possibility that one of the parents is a carrier should be evaluated. The gametes of such a carrier will either carry 2 times the dose, as 21q21q. or chromosome 21 will not be present at all. Such a carrier will not have a chance to have normal children. Therefore, the pregnancy that occurs will either have Down syndrome or (if it survives) Monosomy 21 will be observed. Mosaic carriers are at increased risk of recurrence. Therefore, prenatal diagnosis should be considered in subsequent pregnancies. Mosaic Down Syndrome Cell groups with normal (46 chromosomes) and Trisomy 21 karyotypes are present. The degree and location of mosaicism causes phenotype differences between individuals. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Chromosomes in DOWN SYNDROME Partial Trisomy 21 Very rarely in patients with Down syndrome, only part of the long arm of chromosome 21 is present in triplets. Which part of chromosome 21 is in three copies determines the characteristics of the phenotype. In this way, the ~2Mb region, which is critical for heart diseases observed in ~40% of cases with Down syndrome, was determined. Risk of Recurrence The risk of recurrence for any given trisomy is ~1% overall. It is high in cases of translocation. It is higher (~1.4%) in young (under 30 years) mothers with children with Down syndrome. It is the same as the age-related risk in older mothers. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Edwards Syndrome (Trisomy 18) (Trisomy-E) Trisomy 18 (Edwards syndrome) is a syndrome characterized by multiple congenital anomalies that occur on the background of an excess of chromosome 18. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Edwards Syndrome (Trisomy 18) (Trisomy-E) Common findings in infants with Edwards syndrome: Mental retardation Intrauterine growth retardation, Micrognathia (shortness of the lower jawbone) Microcephaly (head smaller than normal) Low and malformed ears, Cardiac anomalies, Hypertonia (excessive muscle tension) Urinary system anomalies, Gastrointestinal tract anomalies Anomalies of the extremities Hand and foot anomalies are typical ("clenched hand", Clenched hand Clubfoot (club feet) Rocker-bottom feet Hydrops (swelling of the baby's entire body due to heart failure) Omphalocele (the baby's intestines spilling out through an opening in the abdominal wall). - These findings are present in most trisomy 18 infants and are considered a sign that cytogenetic analysis is required. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Edwards Syndrome (Trisomy 18) (Trisomy-E) - While the detection of choroid plexus cysts on routine ultrasound can suggest trisomy 18, amniocentesis may not be necessary if no other abnormalities are found. Incidence: 1 in 6,000 to 8,000 live births. - After trisomy 21, it is the second most common autosomal trisomy among live-born infants. - Approximately 95% of pregnancies with this anomaly result in fetal death before birth, and only 5-10% of babies born with this condition survive beyond one year. - Although it is more commonly associated with advanced maternal age (>35), it has also been observed in mothers as young as 20. - Some of the most significant findings suggesting trisomy 18 during pregnancy include significant fetal growth restriction from early pregnancy and polyhydramnios (excess amniotic fluid). - Trisomy 18 is a severe condition, and unfortunately, 30% of babies die within the first month of life, and 90% within the first year due to various complications such as heart failure. - While life expectancy can be extended to a certain extent with successful surgeries for life-threatening anomalies (such as heart surgery, gastrointestinal surgery), there is no effective treatment for intellectual and motor developmental delays." Edwards Syndrome (Trisomy 18) (Trisomy-E) PATAU SYNDROME (Trisomy 13) (Trisomy-D)  PATAU SYNDROME (Trisomy 13) (Trisomy-D) - Patau Syndrome is the third most common autosomal trisomy following Trisomy 21 and Trisomy 18. - It is seen approximately 1 in 12,000-29,000 live births. - In some affected people, only a fraction of the cells contain the extra chromosome 13 (called mosaic trisomy 13), while other cells contain the normal pair of chromosomes. - Most cases are not hereditary and are caused by a random error during the formation of eggs or sperm in healthy parents. - Due to a variety of life-threatening medical problems, many babies with trisomy 13 do not survive through the first days or weeks of life. - In the study, which followed 300 live-born children with trisomy 13, it was reported that 28% died in the first week of life, 44% in the first month, and 73% in the first 4 months. - The risk of recurrence in pregnancies is low THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  PATAU SYNDROME (Trisomy 13) (Trisomy-D) Common findings observed in Trisomy 13: Severe mental retardation Congenital heart defect The vessel that provides the connection between the aorta and the pulmonary artery, which existed before birth, does not close within a few months after birth (patent ductus arteriosus) Abnormalities of the brain or spinal cord Incomplete development of certain areas of the brain (e.g., forebrain) Congenital deficiency of the rhinencephalon (olfactory brain), which forms part of the mesencephalon (midbrain) Meningomyelocele (opening in spina bifida) Eyes that are too small or poorly developed (microphthalmia) Polydactyly – Extra fingers or toes Rocker-bottom feet Poor muscle tone (hypotonia). THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  PATAU SYNDROME (Trisomy 13) (Trisomy-D) Common findings observed in Trisomy 13: Additional malformations of the head and facial (craniofacial) area Microcephaly (small head diameter and inability of the brain to develop properly) Broad, flat nose widely spaced eyes (ocular hypertelorism) Vertical skin folds covering the eyes Retinal dysplasia Optic nerve hypoplasia Inner corners (epicanthal folds) Scalp imperfections Malformed and drooling ears Holoprozoncephaly (developmental disorder in the frontal part of the brain and midline facial structures Cyclopia Cleft palate or cleft lip without palate Omphalocele (the baby's intestines spilling out through an opening in the abdominal wall) Renal malformations, polycystic kidney Severe feeding difficulties Abnormal genitalia THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  TRISOMY 22 SYNDROME - It was first reported in 1971. - It has been reported in 20 live births in the literature. Phenotypic features: - Mental-motor retardation - Microcephaly - Ear malformation, absence of an external ear canal - Lacrimal canal stenosis - Ptosis (droopy upper eyelid) - Strabismus (strabismus) - Cleft lip - Congenital heart disease. - Non-mosaic patients die in the first year of their lives. - In mosaic patients, there are cases over 20 years of age.  KLINEFELTER SYNDROME Klinefelter syndrome (KS) is the most common sex chromosome disorder in men. It is characterized by the presence of one or more extra X chromosomes. ~80-90 % of patients with KS have the classical form 47,XXY karyotype, 10-20% have the 47,XXY/46,XY mosaic form, and a very small portion have the Klinefelter-like phenotype with other sex chromosome aneuplaids (48,XXXY,48,XXYY,49,XXXXY) and X chromosome constitute structural anomalies.  KLINEFELTER SYNDROME Although the phenotype of individuals with KS is variable, they are usually tall. Clinical manifestations Primary testicular failure, seminiferous tubule dysgenesis, decreased testicular volume, small testes, azoospermia, high FSH, decreased pubic and facial hair growth and penis length, gynecomastia, development, speech impairment and learning difficulties are present. There is also a slight increase in serum estradiol and LH levels. However, these findings are milder in mosaic forms. https://www.osmosis.org/answers/xxy-syndrome  JACOB'S Syndrome (XYY Syndrome) XYY syndrome is a rare chromosomal disorder affecting males (1/1000). Affected individuals are often very tall. Many experience acne problems during adolescence. They may have learning disabilities and behavioral problems. Intelligence is usually within the normal range, but IQ is on average 10-15 points lower than siblings.  TRIPLE X SYNDROME (XXX Syndrome) Trisomy X, the phenotype associated with the chromosomal disorder varies greatly, but most commonly include language-based learning disabilities, developmental dyspraxia, tall stature, low muscle tone (hypotonia), and abnormal bending of the little fingers toward the ring fingers, or clinodactyly. Trisomy X occurs randomly as a result of errors during the division of gonosomal cells in one of the parents. This disorder occurs in 1 in 900 to 1,000 live births.  TURNER SYNDROME (MONOSOMY X) Turner syndrome (TS) occurs as a result of the complete or partial absence of the X chromosome. The incidence in live-born girls is reported to be 1/2500. While 45,X monosomy is detected in 1% of stillbirths, this rate is reported to be approximately 10% in spontaneous abortous. In 50% of the patients, the karyotype is 45,X monosomy. However, most of the TS cases with this karyotype end in spontaneous abortous during the fetal period, and those who survive are thought to be mosaic.  TURNER SYNDROME (MONOSOMY X) Along with clinical findings such as short stature, primary amenorrhea and infertility, phenotypic features such as mane on the neck, low nape hairline, cubitus valgus, and short 4th metacarpal bone may be observed in patients. Deletion and Duplication Syndromes 72 73 74 75 76 77 78 79 80 81 82 83  Duplications and Deletions Figure 6-4Model of rearrangements underlying genomic disorders. Unequal crossing over between misaligned sister chromatids or homologous chromosomes containing highly homologous copies of segmentally duplicated sequences can lead to deletion or duplication products, which differ in the number of copies of genes normally located between the repeats. The copy number of any gene or genes (e.g., A, B, and C) that lie between the copies of the repeat will change as a result of these genome rearrangements. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Duplications and Deletions Duplication occurs when a segment detached from the chromosome as a result of the break adheres to its homologous chromosome. At the end of this, duplication occurs during the gene. This is called tandem duplication (12343456). In reverse tandem duplication, it is 12344356. Duplication also occurs during meiotic events in a parent with a translocation, inversion, or isochromosome. Duplication is much more common than deletion and is usually less harmful. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  Figure 6-5 Chromosomal deletions, duplications, and rearrangements in 22q11.2 mediated by homologous recombination between segmental duplications. A, Normal karyotypes show two copies of 22q11.2, each containing multiple copies of a family of related segmental duplications within the region (dark blue). In DiGeorge syndrome (DGS) or velocardiofacial syndrome (VCFS), a 3-Mb region is deleted from one homologue, removing approximately 30 genes; in approximately 10% of patients, a smaller 1.5-Mb deletion (nested within the larger segment) is deleted. The reciprocal duplication is seen in patients with dup(22)(q11.2q11.2). Tetrasomy for 22q11.2 is seen in patients with cat eye syndrome. Note that the duplicated region in the cat eye syndrome chromosome is in an inverted orientation relative to the duplication seen in dup(22) patients, indicating a more complex genomic rearrangement involving these segmental duplications. B, Expanded view of the 22q11.2 genomic region, indicating the common DGS/VCFS deletions (red) and more distal deletions (also mediated by recombination involving segmental duplications) that are seen in patients with other phenotypes (orange). Genes in the region (from www.genome.ucsc.edu browser) are indicated above the region. C, Two-color fluorescence in situ hybridization analysis of proband with DGS, demonstrating deletion of 22q11.2 on one homologue. Green signal is hybridization to a control region in distal 22q. Red signal shows hybridization to a region in proximal 22q that is present on one copy of the chromosome but deleted from the other (arrow). THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  CRI DU CHAT SYNDROME Cri du chat syndrome (Cat Meow Syndrome, 5p-Syndrome) occurs in newborn babies. It occurs due to the shortness of the short arm of chromosome 5. It occurs in one in ~50000 live babies. When sick babies cry, they make sounds similar to cat meows. A definitive diagnosis is made by genetic testing. Its incidence does not have a regional or racial feature, but it is slightly more common in female babies. There is no definitive treatment for this syndrome. In affected infants and children, treatments are performed to improve the quality of life according to the symptoms. physical therapy strengthens the muscles in the child and makes it easier to perform behaviors such as sitting or standing. In addition, special education, speech therapy and behavioral therapy should be done. If babies with cri du chat syndrome do not have a significant organ injury, they can have a normal life expectancy with proper care and treatment. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  CRI DU CHAT SYNDROME Figure 6-6 Idiopathic deletion syndromes. A-C, Three different children with cri du chat syndrome, which results from deletion of part of chromosome 5p. Note, even among unrelated individuals, the characteristic facies with hypertelorism, epicanthus, and retrognathia. D, Phenotype-karyotype map of chromosome 5p, based on chromosomal microarray analysis of a series of del(5p) patients. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  CRI DU CHAT SYNDROME Symptoms of Cri du chat Syndrome Aggression Developmental and mental retardation Grumpiness Low birth weight Hyperactivity Small head diameter (microcephaly) Slurred speech Weakness in muscle strength There is a typical appearance on the face; Deep-seated eyes The ear level is low. The bridge of the nose is low. The nape is small Hypertelorism (eyes being far apart) is observed A skin fold (epicanthus) is seen in the part of the eyes close to the nose. It has a high and narrow palate structure. Upper teeth close problematically There are often structural disorders in the heart Scoliosis (curvature of the spine) is observed Clinodactyly (Inward or outward curling or change direction of one or more fingers) Syndactyly (conjoined finger), there is a partial pitch between the fingers Visual and hearing impairments are seen. Impaired swallowing and sucking, inability to feed THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  WOLF-HIRSCHHORN SYNDROME (4P-) It is caused by a deletion in the short arm of chromosome 4 (4p16.3 region). Deletions larger than 3 MB are associated with a higher risk of heart defects and cleft palate. It is characterized by typical craniofacial features, prenatal and postnatal growth and mental retardation, severely delayed psychomotor development, seizures, hypotonia, and developmental impairment.  CROUZON'S SYNDROME - Crouzon syndrome is a rare genetic disorder. - It is a form of craniosynostosis in which fibrosis between certain bones of the skull undergoes premature fusion of the joints. - About 30% of individuals with Crouzon syndrome develop hydrocephalus. - In most affected people, there is a premature union of the sutures (i.e. coronal and sagittal sutures) between the bones that make up the forehead (frontal bone) and the upper sides of the skull (parietal bones). - In addition, sutures (in other words, lambdoidal sutures) or other sutures between the dorsal and sides of the skull may interfere with some people. - In most individuals with Crouzon syndrome, the head appears unusually short and wide (brachiocephaly). The head may appear long and narrow (scaphocephaly) triangular (trigonocephaly). - Rarely, premature closure of multiple sutures (known as Kleeblattschadel-type craniosynostosis) causes the skull to split abnormally into three lobes (clover leaf skull deformity). - In patients with Crouzon syndrome, craniosynostosis (premature closure of one or more bones in the skull at the junction (suture) typically begins in the first year of life and progresses to about two to three years of age. However, craniocystosis may sometimes be evident at birth or, rarely, may not be indicated in early childhood.  CROUZON'S SYNDROME Crouzon Syndrome Symptoms The pupils protrude forward Eyes that are crossed or do not point in the same direction (strabismus) Various eye disorders Loss of vision A prominent forehead (frontal bossing) A crooked nose Unusually flat or underdeveloped mid-face area (mid-face hypoplasia) A short upper lip A small, underdeveloped maxillary (hypoplasia maxilla) with an outlet to the lower jaw (relative mandibular prognathism) Split lip and/or palate A curved narrow palate upper and lower teeth that are not met during biting (malocclusion)  PRADER-WILLI SYNDROME Prader-Willi Syndrome is a genetic disorder caused by the incorrect segregation of chromosome 15 during the formation of reproductive cells (eggs or sperm). This typically involves the deletion of a specific region on chromosome 15 inherited from the father. Although it may seem rare, it occurs in approximately 1 in 12,000 to 15,000 live births. Physical Properties: Almond eyes Short stature Loose muscles Prominent and narrow facial features Small hands Small genitalia Thick saliva Eye problems Thin upper lip, small mouth THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  PRADER-WILLI SYNDROME Symptoms: Constant sleep state Respiratory problems Underdevelopment of the genitals General developmental disorder up to 6 years of age Excessive appetite before the age of 6, obesity in later ages Lack of growth hormone high-pitched (thin) tone of voice High or low body temperature THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. PRADER WILLI and ANGELMAN SYNDROMES Figure 6-7 Prader-Willi syndrome (PWS) and Angelman syndrome (AS). A, PWS in a 9.5-year-old boy with obesity, hypogonadism, and small hands and feet who also has short stature and developmental delay. B, Angelman syndrome in a 4-year-old girl. Note wide stance and position of arms. C, Chromosomal microarray detection of approximately 5-Mb deletion in 15q11.2-q13.1 (red). D, Schematic of the 15q11.2-q13 region. The PWS region (shaded in blue) contains a series of imprinted genes (blue) that are expressed only from the paternal copy. The AS region (shaded in pink) contains two imprinted genes that are expressed only from the maternal copy, including the UBE3A gene, which is imprinted in the central nervous system and mutations in which can cause AS. The region is flanked by nonimprinted genes (purple) that are expressed from both maternal and paternal copies. Common deletions of the PWS/AS region, caused by recombination between pairs of segmental duplications, are shown in green at the bottom. Smaller deletions of the imprinting center (IC; orange) and of a subset of genes in the small nucleolar RNA (snoRNA) gene cluster can also lead to PWS. cen, Centromere; tel, telomere. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc. PRADER WILLI and ANGELMAN SYNDROMES THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  1p36 Deletion Syndrome It is one of the most common idiopathic abnormalities. Its incidence in the community is 1/5000. ~95% of all cases occur de novo. Most cases cannot be detected by routine chromosome analysis. Figure 6-6 Idiopathic deletion syndromes. E, Chromosomal microarray analysis of approximately 5-Mb deletion in band 1p36.3 (red), which is undetectable by conventional karyotyping. THOMPSON & THOMPSON GENETICS IN MEDICINE," 8th Ed. Chapter: 6 ISBN: 978-1-4377-0696-3 Copyright © 2016 by Elsevier Inc.  ISOCHROMOSOMES An isochromosome is a mirror-image, abnormal chromosome consisting of two copies of a short arm or two copies of a long arm, often observed for X and acrocentric (13, 14, 15, 21, and 22) chromosomes. Isochromosome X is the most common (approximately 1:13,000) and accounts for more than 15% of cases of Turner syndrome.  RING CHROMOSOMES If there are 2 breaks at the 2 ends of a chromosome, these 2 ends become sticky and join together to form a ring shape. The situation changes depending on the size of the piece broken off as a result of the breakage. The ring chromosome is quite common and has been described in tumors and gonadal dysgenesis.