Genetics_13-14_Chromosomal Disorders_2024.pptx

Genetics Chromosomal Disorders I & II Robin T. Varghese Ph.D. [email protected] u Credit: Pawel Michalak, Ph. D.  Learning Objectives 1. Compare and contrast aneuploidy and polyploidy. 2. Using the proper nomenclature, identify...

Genetics Chromosomal Disorders I & II Robin T. Varghese Ph.D. [email protected] u Credit: Pawel Michalak, Ph. D.  Learning Objectives 1. Compare and contrast aneuploidy and polyploidy. 2. Using the proper nomenclature, identify the most common aneuploid conditions. 3. Identify mitotic and meiotic nondisjunction and the effects of each. 4. Delineate mosaicism and explain how it effects phenotypic expression of a chromosomal disorder. 5. Distinguish between the following chromosomal aberrations: reciprocal and non-reciprocal translocations, Robertsonian translocation, insertion, deletion, paracentric and pericentric inversions, ring chromosome and isochromosome. Summarize the potential complications, if any, which may occur at mitosis and/or meiosis for each aberration. 6. Identify chimerism and differentiate between the two most common causes/forms. Categories of Genetic Diseases 1. Single-Gene Disorder 2. Multifactorial Disorder 3. Chromosomal Disorder a. Structural Abnormalities b. Numerical Abnormalities Chromosome Abnormalities Abnormalities of chromosome numbers Euploid – a balanced genomic state an exact correct multiple of the basic chromosome set. e.g., in humans: 2n = 46 Aneuploid – The occurrence of one or more extra or missing chromosomes in a cell Polyploidy: condition of possessing more than two complete sets of chromosomes e.g.,Triploidy and Tetraploidy, occasionally observed in clinical material (fetuses)  Triploidy 1% to 3% of recognized conceptions; triploid infants can be liveborn, but do not survive long. Among the few that survive at least to the end of the first trimester of pregnancy, most result from fertilization of an egg by two sperm (dispermy). Other cases result from failure of one of the meiotic divisions in either sex, resulting in a diploid egg or sperm. ryotype from a spontaneous miscarriage showing triploidy.  Aneuploidy 5% of all clinically recognized pregnancies. Most aneuploid patients have either trisomy (three instead of the normal pair of a particular chromosome) or, less often, monosomy (only one representative of a particular chromosome). Either trisomy or monosomy can have severe phenotypic consequences. 45, XX, -14 Examples of a trisomy and a monosomy, including nomenclature. Parental origins of common aneuploidies.  Meiotic Nondisjunction The different consequences of nondisjunction at meiosis I (center) and meiosis II (right), compared with normal disjunction (left). If the error occurs at meiosis I, the gametes either contain a representative of both members of the chromosome 21 pair or lack a chromosome 21 altogether. If nondisjunction occurs at meiosis II, the abnormal gametes contain two copies of one parental chromosome 21 (and no copy of the other) or lack a chromosome 21. Down’s syndrome = trisomy 21 Increased risk of meiotic nondisjunction increases with increased maternal age.  Individuals with Patau syndrome often have: Intellectual disability heart defects, brain or spinal cord abnormalities, very small or poorly developed eyes (microphthalmia), extra fingers or toes, an opening in the lip (a cleft lip) with or without an opening in the roof of the mouth (a cleft palate), and weak muscle tone (hypotonia). Many infants with trisomy 13 die within their first days or weeks of life. Only 5-10 percent of children with this condition live past their first year. Patau syndrome = trisomy 13 Edward’s syndrome = trisomy 18  Fluorescent in-situ hybridization (FISH) of interphase nuclei with centromeric probes for chromosomes 18, X and Y showing three aqua signals consistent with trisomy 18. Klinefelter Syndrome (XXY) Turner Syndrome (XO) -tall -short stature (SHOX) -long extremities -amenorrhea -infertility -infertility -hypogonadism -webbed neck Triple X syndrome (XXX) Double Y Males (XYY) -phenotypically normal but maybe -phenotypically normal (often undiagnosed) taller than average -may be associated w/ acne and learning -may be associated increased risk disabilities of learning disabilities -two bar bodies XXX and XYY karyotypes Feature 47,XXY 47,XYY 47,XXX 45,X Klinefelter Trisomy X Turner Syndrome Syndrome Prevalence 1 in 600 male births 1 in 1000 male births 1 in 1000 female 1 in 2500 to 4000 births female births Clinical phenotype Tall male Tall, but otherwise Hypotonia, delayed Short stature, webbed typical male milestones; language neck, lymphedema; appearance and learning risk for cardiac difficulties; tend to be abnormalities taller than average Cognition/intelligence Verbal IQ reduced to Verbal IQ reduced to Normal to low-normal Typically normal, but low-normal range; low-normal range; range (both verbal performance IQ lower educational language delay; and performance IQ than verbal IQ difficulties reading difficulties decreased) Behavioral phenotype No major disorders; Subset with specific Typically, no Typically normal, but tendency to poor behavioral problems behavioral problems; impaired social social adjustments, likely associated with some anxiety and low adjustment but normal adult lower IQ self-esteem; reduced relationships social skills Sex Hypogonadism, Normal ?Reduced fertility in Gonadal dysgenesis, development/fertility azoospermia, some delayed maturation, infertility ?Premature ovarian infertility failure al Complication in Diagnosis of chromosomal disorder: Mosaicism and Chimerism Mosaicism- the presence of two or more population of cells (differ genetically) found in one individual. Caused by a mitotic error or mutation in at least one cell early on embryological development e.g., a cell gainsMosaicism or losesis aderived chromosome (e.g., from a single zygotevia nondisjunction). Types of Mosaicism -Somatic mosaicism- Potentially symptomatic. Not inheritable -Germinal mosaicism- Asymptomatic but could be transmitted to progeny. Chimera is an organism that is composed of cells derived from two (genetically different sources) zygotes. Only ~100 documented cases.  Mosaicism (46,X Mosaic Down X) syndrome is Mosaic Down (46,X syndrome may caused by a X) nondisjunction *Nondisjunction have the same event that occurs (47,XX, features health during one of the +21) risks seen in initial cell babies born with divisions after other types of fertilization Down syndrome but usually presents as less severe. Mosaic form of Down Syndrome ( seen in ~1% of individuals with Down syndrome) Chromosome structural changes Structural rearrangements are classified as balanced, if the genome has the normal complement of chromosomal material, or unbalanced, if there is additional or missing material. Haploinsufficiency?  Metaphase image of Williams (ELN) region probe (Vysis), chromosome band 7q11.23, showing the deletion associated with Williams syndrome. The normal chromosome has signals for the control probe (green) and the ELN gene probe (orange), but the deleted chromosome shows only the control probe Williams Beuren signal.Syndrome https://raisingchildren.net.au/disability/guide-to-disabilities/assessment-diagnosis/willia Chromosomal deletions, duplications, and rearrangements in 22q11.2 mediated by homologous recombination between segmental duplications. https://en.wikipedia.org/wiki/Cat_eye_syndrome Formation of an isochromosome. Formation of a ring chromosome. Chromosome painting showing two #17 chromosomes and a small ring #17 (arrow).  Translocation involves the exchange of chromosome segments between two chromosomes. There are two main types: reciprocal and Robertsonian. Types of translocation. Balanced translocation between two chromosomes, with a reciprocal exchange  t(9;22)(q34;q11) Multicolor spectral karyotyping demonstrating a reciprocal translocation. Example of a Robertsonian translocation A 14q21q Robertsonian translocation its effects on offspring. Pericentric and paracentric inversions. Illustration of why pericentric and paracentric inversions result  General Guidelines for Counseling Monosomies are more deleterious than trisomies. Complete monosomies are generally not viable, except for monosomy for the X chromosome. Complete trisomies are viable for chromosomes 13, 18, 21, X, and Y. The phenotype in partial aneuploidy depends on a number of factors, such as the size of the unbalanced segment, which regions of the genome are affected and which genes are involved, and whether the imbalance is monosomic or trisomic. Risk in cases of inversions depends on the location of the inversion with respect to the centromere and on the size of the inverted segment. For inversions that do not involve the centromere (paracentric inversions), there is a very low risk for an abnormal phenotype in the next generation. But, for inversions that do involve the centromere (pericentric inversions), the risk for birth defects in offspring may be significant and increases with the size of the inverted segment. For a mosaic karyotype involving any chromosome abnormality, all bets are off! Counseling is particularly challenging because the degree of mosaicism in relevant tissues or relevant stages of development is generally unknown. Thus there is uncertainty about the  References The hyperlinks embedded within the lecture notes Word document provide ample references for this material.