Chromosomal Aberrations Lecture Notes PDF

Lect. 7: Chromosomal Aberrations Dr./ Ahmed Mahdy  Chromosomal abnormalities Numerical Structural abnormalities abnormalities It’s the change in the When part of an individual number...

Lect. 7: Chromosomal Aberrations Dr./ Ahmed Mahdy  Chromosomal abnormalities Numerical Structural abnormalities abnormalities It’s the change in the When part of an individual number of chromosomes chromosome is missing, extra, e.g. trisomy, monosomy switched to another chromosome, or turned upside down. ❑ Numerical abnormalities ❑ Structural abnormalities Four different kinds of structural changes of chromosome have been demonstrated: a) Deficiency (parts of chromosome lost or deleted). b) Duplication (parts of chromosome added or duplicated). c) Inversion (sections of chromosome detached and reunited in reverse order). d) Translocation (parts of chromosome detached and joined to non-homologous chromosome). ❑ Deficiency or Deletion: It is the loss of a segment of chromosome. 1. Terminal deletion: Lost segment includes telomere. 2. Interstitial (intercalay) deletion: A segment between telomere and centromere is lost. In presence of a deficiency, a recessive allele will behave like a dominant allele and this phenomenon is called pseudodominance. ❑ Pseudodominance: The sudden appearance of a recessive phenotype in a pedigree, due to deletion of a masking dominant gene. ❑ Duplication: A chromosome segment present in more than 2 copies in the same nucleus. Types: Tandem duplication - adjacent region. Reverse tandem duplication – duplicated segment found as a reverse repeat at adjacent region. Displaced homobrachial duplication – at a displaced position of the same arm. Displaced heterobrachial duplication - on the different arm of the same chromosome; Transposed duplication - on a different chromosome; Fig. : Different kinds of duplications. ❑ Inversion: A chromosome segment contains genes in a sequence which is reverse of the normal. 1. Paracentric inversion :The inverted segment does not contain centromere. 2. Pericentric inversion: The inverted segment contains centromere. ❑ Translocation: Chromosome segment integrated into non-homologous chromosomes. Types: (i) Simple translocation - The broken part gets attached to one end of non- homologous chromosome. (ii) Shift translocation - Broken part gets inserted interstitially in a non- homologous chromosome. (iii) Reciprocal translocation - When parts of chromosomes belonging to members of two different pairs become exchanged. a segment of a chromosome detaches and attaches to a completely different chromosome ❑ Translocation to Homologous Chromosome: If a translocation were to occur between homologous chromosomes (i.e., chromosomes that are similar and pair up during meiosis), it called "homologous recombination" or "crossing over". This is a normal process that occurs during meiosis where genetic material is exchanged between homologous chromosomes to create genetic diversity. However, unusual translocation-like events between homologous chromosomes may still be described as "ectopic recombination" or "ectopic translocation" if the genetic material is rearranged or exchanged in a way that doesn't follow the usual recombination process. This can lead to structural changes or abnormalities in the chromosomes.  Karyotyping A karyotype is an image of a person’s chromosomes numbered and arranged according to size that can be used to detect chromosomal abnormalities. The karyotype is the arrangement of metaphase chromosomes in homologous pairs according to size and location of centromere. Case studies of Chromosomal aberrations  o Chromosomal Numerical Disorders Down syndrome (Trisomy 21): (47,XX +21 or 47,XY +21) o Occurs when a person has an extra copy of chromosome 21. Klinefelter syndrome (XXY): 47,XXY (or 48,XXXY) o Occurs in males who have an extra X chromosome. Turner syndrome (45, X0): o Occurs in females who are missing all or part of an X chromosome. Jacobs syndrome (47,XYY): o characterized by the presence of an extra Y chromosome. Edwards syndrome (Trisomy 18): (47,XY+18 or 47,XX+18) o characterized by the presence of an extra copy of chromosome 18. Patau syndrome (Trisomy 13): (47,XY+13 or 47,XX+13) o caused by the presence of an extra copy of chromosome 13. ❑ Down’s syndrome ❑ Down’s syndrome Typically there are epicanthal folds and a flat, broad face. Delays in speech & attention problems. Protruding tongue. Hypotonia (poor muscle tone).  Down syndrome is a chromosomal condition that is associated with cognitive delays and mild to moderate intellectual disability, and weak muscle tone (hypotonia) in infancy. Down syndrome often have a characteristic facial appearance that includes a flattened appearance to the face, outside corners of the eyes that point upward (upslanting palpebral fissures), small ears, a short neck, and a tongue that tends to stick out of the mouth. Many people with Down syndrome have small hands and feet and a single crease across the palms of the hands. About half of all affected children are born with a heart defect. Individuals with Down syndrome have an increased risk of developing several medical conditions. These include gastroesophageal reflux, which is a backflow of acidic stomach contents into the esophagus, and celiac disease, which is an intolerance of a wheat protein called gluten. About 15 percent of people with Down syndrome have an underactive thyroid gland (hypothyroidism).  Down syndrome is also associated with an increased risk of developing Alzheimer's disease earlier, in their fifties or sixties, a brain disorder that results in a gradual loss of memory, judgment, and ability to function. There are three types of Down syndrome. The physical features and behaviors are similar for all three types. Trisomy 21, each cell in the body has three separate copies of chromosome 21. About 95% of people with Down syndrome have Trisomy 21. Translocation Down syndrome, In this type, an extra part or a whole extra chromosome 21 is present. However, the extra chromosome is attached or "trans-located" to a different chromosome rather than being a separate chromosome 21. This type accounts for about 3% of people with Down syndrome. Mosaic Down syndrome, means mixture or combination. In this type, some cells have three copies of chromosome 21, but other cells have the typical two copies. People with mosaic Down syndrome may have fewer features of the condition. This type accounts for about 2% of people with Down syndrome. Risk factors One factor is age. The risk of having a baby with Down syndrome increases with age, especially 35 years or older female when she get pregnant. However, the majority of babies with Down syndrome are still born to mothers less than 35 years old. This is because there are many more births among younger women. Regardless of age, parents who have one child with Down syndrome are at an increased risk of having another child with Down syndrome. Which syndrome will likely be developed as a result of the chromosomal abnormality shown in the karyotype provided? A.Down syndrome B.Turner syndrome C.Klinefelter syndrome D.Jacobs syndrome ❑ Klinefelter syndrome Klinefelter syndrome is a common condition that results when a person assigned male at birth has an extra copy of the X sex chromosome instead of the typical XY. Klinefelter syndrome is a genetic condition that occurs before birth, but it often isn't diagnosed until puberty or adulthood. Klinefelter syndrome may affect testicular growth. This results in smaller testicles, which can lead to making less testosterone hormone and produce little or no sperm. The syndrome also may cause smaller muscle mass, less body and facial hair, gynecomastia, infertility, osteoporosis and learning difficulties and extra breast tissue. ❑ Klinefelter syndrome = gynecomastia ❑ Klinefelter karyotype  ❑ Turner syndrome Turner syndrome, a condition that affects only females, results when one of the X chromosomes (sex chromosomes) is missing or partially missing. Phenotype is basically female, but patients fail to mature sexually. Turner syndrome can cause a variety of medical and developmental problems, including short height, failure of the ovaries to develop and heart defects. Turner syndrome has characteristics Facial features include: Drooping eyelids, High, narrow roof of the mouth, Low hairline, Low-set ears and Small jaw. About 30 percent of individuals with Turner syndrome have extra folds of skin on the neck (webbed neck), a low hairline at the back of the neck, puffiness or swelling (lymphedema) (excess fluid) of the hands and feet of newborns, skeletal abnormalities, or kidney problems. ❑ Turner syndrome ❑ Turner Karyotype  ❑ Jacobs syndrome 47,XYY syndrome is characterized by an extra copy of the Y chromosome in each of an individual's cells, the chromosomal change sometimes causes no unusual physical features. Most individuals with 47,XYY syndrome have normal production of the male sex hormone testosterone and normal male sexual development, and they are usually able to father children. ❑ Jacobs syndrome ❑ Boys with XYY syndrome may have some or all of these physical symptoms to some degree: taller than average height testicular atrophy low muscle tone, or muscle weakness (called hypotonia) unusually large teeth (macrodontia) flat feet (pes planus) very curved pinky finger (called clinodactyly) widely spaced eyes (called hypertelorism) abnormal curvature of the spine (scoliosis). ❑ 47,XYY syndrome is associated with an increased risk of learning disabilities and delayed development of speech and language skills. ❑ Affected children can have delayed development of motor skills (such as sitting and walking) or weak muscle tone (hypotonia). ❑ Other signs and symptoms of this condition include hand tremors or other involuntary movements (motor tics), seizures, and asthma. ❑ Individuals with 47,XYY syndrome have an increased risk of behavioral, social, and emotional difficulties compared with their unaffected peers.  ❑ Edwards syndrome Edwards syndrome: also known as Trisomy 18, is another chromosomal disorder characterized by the presence of an extra copy of chromosome 18.  Edwards syndrome is a form of aneuploidy, specifically trisomy 18, where individuals have three copies of chromosome 18. This condition is usually caused by non-disjunction during meiosis, where chromosomes fail to separate properly, resulting in an extra chromosome 18 in each cell. ❑ Types of Edwards' syndrome Full Edwards' syndrome Most babies with Edwards' syndrome have an extra chromosome 18 present in all cells. The effects are often more severe, most babies with this form will die before they are born. Mosaic Edwards' syndrome Trisomy 18 can also appear in mosaic form (not all cells carry the extra chromosome). This can lead to milder effects of the condition, depending on the number and type of cells that have the extra chromosome. Most babies with this type of Edward's syndrome who are born alive will live for at least a year, and they may live to adulthood.  Partial Edwards' syndrome A very small number of babies with Edwards' syndrome (about 1 in 100) have only a section of the extra chromosome 18 in their cells, rather than a whole extra chromosome 18. This is called partial Edwards' syndrome (or sometimes partial trisomy 18). ❑ Symptoms of Edwards syndrome (trisomy 18) during pregnancy Signs of Edwards syndrome (trisomy 18) During a prenatal ultrasound including: Very little fetal activity, A single artery in umbilical cord, A small placenta, Birth defects, fetus is surrounded by too much amniotic fluid (polyhydramnios). ❑ Characteristics of Edwards syndrome (trisomy 18) after birth), including: Decreased muscle tone (hypotonia). Low-set ears. Internal organs forming or functioning differently (heart and lungs). Issues with cognitive development (intellectual disabilities). Overlapping fingers and/or clubfeet. Small physical size (head, mouth and jaw). Weak cry and minimal response to sound. ❑ Severe symptoms of Edwards syndrome (trisomy 18) Because children diagnosed with Edwards syndrome (trisomy 18) have underdeveloped bodies, the side effects of the condition have serious and often leads to a shortened life expectancy due to the associated complex health issues including: Severe developmental delays Congenital heart disease and kidney disease (present at birth). Breathing abnormalities (respiratory failure). Gastrointestinal tract and abdominal wall issues and birth defects. Hernias. Scoliosis (sideways curvature of the spine). ❑ Patau syndrome  ❑ Patau syndrome Patau syndrome, also known as Trisomy 13, is a chromosomal disorder caused by the presence of an extra copy of chromosome 13. It occurs due to non-disjunction during cell division (meiosis), where chromosome pairs fail to separate correctly, leading to an extra chromosome. In some cases, Patau syndrome may present as mosaic trisomy 13 (not all cells have the extra chromosome) or as partial trisomy 13 (only a segment of chromosome 13 is duplicated). This chromosomal abnormality disrupts normal development, leading to severe intellectual disabilities and physical abnormalities. Since internal organ symptoms can be life-threatening, nearly 80% of babies diagnosed with Trisomy 13 don’t survive past their first year. Those that do survive may face more life-threatening complications after their first year including an increased risk of developing cancer and seizures. Symptoms of trisomy 13 include: Heart abnormalities present at birth (congenital). brain or spinal cord abnormalities Severe issues with cognitive function. Underdeveloped internal organs. ❑Physical symptoms Cleft lip or cleft palate. very small or poorly developed eyes (microphthalmia) Difficulty gaining weight. Extra fingers or toes (polydactyly). Ears forming low on the head. Growth abnormalities in the arms and legs. Low muscle tone (hypotonia). Small head and lower jaw. Very small, close together or underdeveloped eyes. ❑Internal organ symptoms Gastrointestinal (GI) problems that make eating difficult. Heart failure. Hearing problems. Underdeveloped lungs. Vision problems. Chromosomal Structural Disorders  Chromosomal Structural Disorders ❑Cri du chat syndrome: Occurs when a piece of chromosome 5 is missing. ❑Wolf-Hirschhorn syndrome: Occurs when a piece of chromosome 4 is missing. ❑Angelman: deletion of part of chromosome 15 ❑Digeorge: Microdeletion on the long arm of chromosome 22  ❑ Cri du chat syndrome Cri du chat syndrome 5p- (5p minus), or cat cry syndrome, is a rare genetic disorder that happens because of a missing piece (deletion) of a chromosome 5. It gets its name from the distinct cry that infants with malformed larynxes cause them to cry with a sound like a cat or high-pitched mewing of a cat. “Cri du chat” means “cry of the cat” in French. They have abnormalities of the palate & malformations of the ears. ❑ Cri du chat Karyotype ❑ Wolf-Hirschhorn syndrome (WHS) Wolf-Hirschhorn syndrome (WHS), also known as deletion 4p syndrome, is a disorder caused by irregularities on the short arm of chromosome 4. It can affects several parts of your child’s body, including face, heart, brain and height. It is characterized by a distinctive facial appearance (the Greek warrior helmet), growth delay, intellectual disability, hypotonia, and seizures.  Angelman syndrome is a complex genetic disorder that primarily affects the nervous ❑ Angelman syndrome (AS) system. Characteristic features of this condition Angelman syndrome (AS) is a rare neuro- include delayed development, intellectual genetic disorder that occurs in one in disability, severe speech impairment, and 15,000 live births or 500,000 people problems with movement and balance worldwide. (ataxia). It is caused by a loss of function of the Most affected children also have recurrent UBE3A gene in the 15th chromosome seizures (epilepsy) and a small head size derived from the mother. (microcephaly). Delayed development becomes noticeable by the age of 6 to 12 months.  ❑ DiGeorge syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a condition caused by a microdeletion on the long arm of chromosome 22. Medical problems commonly related to 22q11.2 deletion syndrome include heart problems, lowered immunity, a cleft palate, complications from low levels of calcium, various eye issues and autoimmune disorders. Mouth and feeding problems – including a gap in the top of the mouth or lip (cleft lip or palate). Complications also include hearing loss, skeletal differences, kidney and genital differences, and delayed development with behavioral and emotional problems. Also Learning and behavior problems. ❑ DiGeorge syndrome