Chromosomal Disorders PDF

Chromosomal Disorders Dr. Suheir Ereqat 2023/2024  Causes of Chromosomal Disorders Ionising radiation, virus infections and chemical toxins in the pathogenesis of certain disorders. Most cases of simple aneuploidy - monosomy or trisomy - are likely due to meiotic non-disjunct...

Chromosomal Disorders Dr. Suheir Ereqat 2023/2024  Causes of Chromosomal Disorders Ionising radiation, virus infections and chemical toxins in the pathogenesis of certain disorders. Most cases of simple aneuploidy - monosomy or trisomy - are likely due to meiotic non-disjunctions Mitotic nondisjunction: it could happened!! Dr. Suheir Ereqat 2023/2024 Clinical presentation suggestive of chromosomal abnormality Infertility and sterility: Cytogenetic analysis of such individuals is often warranted Intersexes: genetic and phenotypic sex do not correspond. Multiple congenital malformations: seen with many types of chromosomal abnormalities, particularly deletions and aneuploidy. Mental retardation: Well-known examples of this are Down and fragile X syndromes. Dr. Suheir Ereqat 2023/2024 Sterility vs infertility Dr. Suheir Ereqat 2023/2024  14 and 16 weeks gestation 0.25%-0.50% risk of miscarriage Chorionic villus sampling uses what tissue to analyze the fetal cells and provide a karyotype? A) fetal blood tissue B) cells floating in the amniotic fluid C) a small biopsy from the embryo itself but it readily heals D) membrane tissues from the embryo side of the placenta E) membrane tissues from the mother's side of the placenta Answer: D Dr. Suheir Ereqat 2023/2024 10–12 weeks' gestation Risk: miscarriage (1-2%) Infection Amniotic fluid leakage Dr. Suheir Ereqat 2023/2024  Chromosomal abnormalities 1. Alterations in chromosome number. Euploid - normal set (2n) Polyploidy – extra set of the entire genome. (3n, 4n etc) (triploidy,tetraploidy) Aneuploidy – less or more than the normal diploid number. -Monosomy - one member of a chromosome pair is missing (2n-1) -Trisomy - one chromosome set consists of 3 copies of a chromosome (2n+1) Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024  Triploidy: [23 X3] 69XXX Fertilization by two sperm cells or fertilization of a diploid egg Dr. Suheir Ereqat 2023/2024 =n+1 =n-1 Dr. Suheir Ereqat 2023/2024  =2n+1= Dr. Suheir Ereqat 2023/2024 Aneuploidy - Trisomy 13 Dr. Suheir Ereqat 2023/2024 Cleft lip and palate Small eyes Extra fingers & toes polydactylism Defects Heart Brain Kidney Most abort Live span < 1 month  2. Anomalies of chromosome structure Translocations Robertsonian Reciprocal (balanced and un balanced) Deletions Duplications Ring chromosomes Inversion : paracentric and pericentric. Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024  Deletion 1. End of chromosome or ends of chromosome pair break off 2. Cri du chat- portion of chromosome 5 deleted Dr. Suheir Ereqat 2023/2024  Deletion Dr. Suheir Ereqat 2023/2024  Effect of deletion If the deletion includes the centromere, the chromosome will not segregate in meiosis or mitosis and will usually be lost. Lethal (homozygous condition) imbalances in the amounts of gene products (heterozygous condition) -haploinsufficient gene=single copy not sufficient to produce wild type phenotype. -Pseudodominance=recessive mutations not masked Dr. Suheir Ereqat 2023/2024  Cri du Chat Cry of the Cat individuals sound like cats crying. Why? The larynx of the child is improperly developed. Dr. Suheir Ereqat 2023/2024  Cri-Du-Chat Syndrome 1 in 216,000 births 46 chromosomes #5 Deletion of band p15.3 The deletion occurs most often as a random Symptoms: Moon-shaped face Heart disease Mentally retarded Malformed larynx Normal lifespan Dr. Suheir Ereqat 2023/2024  Duplication 1. Mispairing- unequal cross-over results in chromosome segment repeats 2. Tandem , displaced, reverse ABC.DEFGH ABC.DEFEFGH ABC.DEFGHEF ABC.DEFFEGH Dr. Suheir Ereqat 2023/2024 Duplication Dr. Suheir Ereqat 2023/2024  Question? How does a chromosome duplication alter the phenotype? Dr. Suheir Ereqat 2023/2024  Answer Unbalanced gene dosage= developmental abnormalities. an individual organism with three functional copies of a gene often produces 1.5 times as much of the protein encoded by that gene as that produced by an individual with two copies. Because developmental processes require the interaction of many proteins, they often depend critically on proper gene dosage Dr. Suheir Ereqat 2023/2024  Inversion 1. Chromosome segment breaks apart 2. Rejoins in reversed direction, turned 180o 3. Same genes present, but sequence of genes is reversed 4. position effect: may be expressed at inappropriate times or in inappropriate tissues. Dr. Suheir Ereqat 2023/2024  Chromosomal Inversions Paracentric inversion does not involve centromere Pericentric inversion involves centromeric region Dr. Suheir Ereqat 2023/2024  Translocation -1. Movement of segment from one chromosome to another nonhomologous chromosomes -3-4% of Down syndrome (familial) result of translocation between chromosomes 21 and 14 ( a segment of chr. 21 detaches and fuses with chr. 14= fused chr.=14/21) Dr. Suheir Ereqat 2023/2024  Reciprocal translocation How the 1;22 translocation originated Chromosome 1 and 22 broke at the positions indicated by the arrows, and the cell’s DNA repair machinery rejoined the ends to form the two derivative chromosomes as shown. The derivative chromosomes are labelled der(1) and der(22). Dr. Suheir Ereqat 2023/2024 Robertsonian translocation: centric fusion A centric fusion is a translocation in which the centromeres of two acrocentric chromosomes fuse to generate one large metacentric chromosome Dr. Suheir Ereqat 2023/2024 A Robertsonian translocation The inset shows how this common type of chromosome abnormality arises. The short arms of all the acrocentric chromosomes (13, 14, 15, 21, 22) contain similar DNA. Inappropriate recombination between two non-homologous chromosomes produces the fusion chromosome, which functions as a normal single chromosome in mitosis. The small acentric fragment comprising the two distal short arms is lost. Dr. Suheir Ereqat 2023/2024 Translocation in Meiosis: cross like structure Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024  you can imagine … r. Suheir Ereqat 2023/2024 Most frequent numerical anomalies in live born Autosomes Down syndrome (trisomy 21: 47,XX,+21) Edwards syndrome (trisomy 18: 47,XX,+18) Patau syndrome (trisomy 13: 47,XX+13) Sex chromosomes Turner syndrome 45,X Klinefelter syndrome 47,XXY Dr. Suheir Ereqat 2023/2024 VARIATIONS ON SEX CHROMOSOME NUMBERS Klinefelter syndrom. (47,XXY) Genital and internal ducts are present as in males. Their testes are underdeveloped and fail to produce sperms. They have enlarged breast. Mentally retarded. Feminine sexual development is not entirely suppressed. Dr. Suheir Ereqat 2023/2024  Klinefelter Syndrome 1 in 1,100 births 47 chromosomes XXY only #23 Trisomy Nondisjunction No facial hair Longer fingers and arms Sterile Low mental ability Normal lifespan Dr. Suheir Ereqat 2023/2024 Wide hip and feminine fat distribution Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024  Turner syndrome XO (45,X). Female external genetelia, and internal ducts, but ovaries are redundant. Short status. Under 5 feets. Dr. Suheir Ereqat 2023/2024  Turners Syndrome 1 in 5,000 births 45 chromosomes X only #23 Monosomy Nondisjunction 96-98% do not survive to birth No menstruation No breast development Narrow hips Broad shoulders and neck Learning difficulties in school Dr. Suheir Ereqat 2023/2024 Webbed neck  Jacob’s Syndrome 1 in 1,800 births 47 chromosomes XYY only #23 Trisomy Nondisjunction ? Normal physically Normal mentally normal sexual development. Increase in testosterone More aggressive Dr. Suheir Ereqat 2023/2024 Normal lifespan  xyy X XYY X YY sperm Egg Dr. Suheir Ereqat 2023/2024  Triple X Syndrome Normal physically Sometimes taller Normal mentally Fertile(menstrual irregularities) Dr. Suheir Ereqat 2023/2024  If nondisjunction was mother  P: XBXb x XBY  c. XB Y XB Xb XBXBXb XBXbY Super female Klinefelter 0 XB0 0Y Turner Lethal Dr. Suheir Ereqat 2023/2024 If nondisjunction was father P: XBXb x XBY XBY 0 XB XBXBY XB0 Klinefelter Turner Xb XBXbY Xb0 Klinefelter Turner Dr. Suheir Ereqat 2023/2024  Dosage Compensation  Shouldn’t XX females produce twice the amount of X-linked gene products (proteins) as XY males?  No, because XX females “compensate” by inactivating one of their X chromosomes to make a single “dosage” of X- linked genes. Dr. Suheir Ereqat 2023/2024  Inconsistencies between syndromes and X inactivation If normal XX female has one X inactivated, why is a X Turner female not normal? Similarly, if XXY male has one X inactivated, why does he have Klinefelter syndrome? Random inactivation Perhaps not complete inactivation Or inactivation does not happen immediately, Then some overexpression of X-linked genes Dr. Suheir Ereqat 2023/2024 Trisomy: In general, more viable than monosomy Down Syndrome (47, xx +21) Characteristic facial patterning (flattened) 1 / 800 live births Dr. Suheir Ereqat 2023/2024  Down Syndrome, Mongolism Characteristics  Most often occurs by nondisjunction of chr. 21 during meiosis; in theory could occur in either mom or dad, but 95% of these trisomies have defective egg as source.  Prone to respiratory diseases, etc.  About 30% of all cases of mental retardation in U.S.  1/25 can read; 1/50 can write Dr. Suheir Ereqat 2023/2024 Nondisjunction Dr. Suheir Ereqat 2023/2024 Incidence of Down Syndrome Increases with Maternal Age All eggs are formed by birth and arrested in meiosis; is the correlation of increased age and the syndrome due to more non- disjunction in older eggs? Dr. Suheir Ereqat 2023/2024  Familial Down Syndrome 1 in 31,000 births 46 chromosomes XY=97% XX=3% #14/21 Translocation Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024  Mosaicism * mutation in single gene * chromosomal anomaly Mosaicism can be: somatic (ie in most body cells) or gonadal (confined solely to the gonads). Dr. Suheir Ereqat 2023/2024 Turner: 30% Reduced fertility Delayed or absent periods Dr. Suheir Ereqat 2023/2024 Dr. Suheir Ereqat 2023/2024  The Karyotype: an international description Total number of chromosomes, Sex chromosome constitution, Anormalies/variants. += additional material 46,XY 47,XX,+21 47,XXX 69,XXY 45,XX,der(22) 46,XY,t(2;4)(p12;q12) 46,XX,del(5)(p25) 46,XX,dup(2)(p22) 46,XY,inv(11)(p15q14) 46,XY/47,XXY Dr. Suheir Ereqat 2023/2024  The Karyotype: an international description 46,XY Normal 47,XX,+21 Trisomy 21 (Down syndrome) 47,XXX Triple X syndrome 69,XXY Triploidy 45,XX,der(22) chromosome derived from ch22 -contains its cent. 46,XY,t(2;4)(p12;q12) Reciprocal translocation 46,XX,del(5)(p25) Deletion tip of chromosome 5 46,XX,dup(2)(p22) Duplication of part of short arm Chr 2 46,XY,inv(11)(p15q14) Pericentric inversion chromosome 11 46,XY/47,XXY Mosaicism normal/Klinefelter syndrome 46,xx/45,x Mosaicism normal/ Turner syndrome Dr. Suheir Ereqat 2023/2024 Epigenetics:Genomic imprinting Some genes are expressed only from the maternal genome and some only from the paternal genome It is estimated that about 40 genes are imprinted and they can be found on several different chromosomes For example - Insulin-like growth factor (Igf2) gene Dr. Suheir Ereqat 2023/2024 insulin like growth factor2 Dr. Suheir Ereqat 2023/2024  Imprinting is maintained by DNA methylation Chromatin remodeling=dynamic modification of chromatin = control gene expression Heterochromatin=more condensed=repressed gene Euchromatin=loose=active gene Dr. Suheir Ereqat 2023/2024  Angelman Syndrome Developmental delay Functionally severe Speech impairment frequent laughter/smileing; apparent happy demeanor; easily excitable personality Dr. Suheir Ereqat 2023/2024  Angelman Syndrome –Angelman Syndrome- maternal chromosome deletion Or an imprinting defect Normal chromosome 15 Or 2 paternal chromosomes Dr. Suheir Ereqat 2023/2024  Prader-Willi Syndrome Poor weight gain in infancy Excessive or rapid weight gain between 1 and 6 Delayed sexual maturity Mild to moderate mental retardation Obsession with food (hyperphagia )- Diabetes For the genes affected in PWS, paternal copy of this gene is deleted and the maternal copy that is usually imprinted (and thus is silenced) Dr. Suheir Ereqat 2023/2024