Downloaded 80 times
![Mosaicism
• Individual with 2 or more cell types originating from a
single zygote
• Different chromosome number (or structure)
• Usually after conception, happens in embryo
• Non-disjunction during mitosis in the zygote
• 47,XX+21 [10] / 46,XX [20]
• Unpredictable phenotype](https://image.slidesharecdn.com/06102014finalreprochromosomeanomalies-141014061702-conversion-gate01/85/repro-chromosome-anomalies-21-320.jpg)
![Mosaic Down syndrome
• 47,XY,+21[10] / 46,XY [20]
mitosis](https://image.slidesharecdn.com/06102014finalreprochromosomeanomalies-141014061702-conversion-gate01/85/repro-chromosome-anomalies-44-320.jpg)
![Turner syndrome
• 1 in 2500 live female births
• 45,X and variants
• Mosaic, count 30 cells
• Structural X anomaly
45,X[10]/46,XX[20]
45X/46,XY
46,X,i(X)
45,X/46,X,r(X)
• Antenatal – 99% TS conceptions loss, intrauterine
lethality 14-40w of 65%](https://image.slidesharecdn.com/06102014finalreprochromosomeanomalies-141014061702-conversion-gate01/85/repro-chromosome-anomalies-76-320.jpg)
Uploaded byXolani Hadebe
repro chromosome anomalies
This document discusses various genetic disorders and conditions, including both numerical and structural chromosomal disorders. It provides classifications of genetic disorders, descriptions of specific disorders like Down syndrome, Edward syndrome, and Patau syndrome. Details are given on karyotypes, cytogenetics, causes and characteristics of different chromosomal abnormalities.
More Related Content
Similar to repro chromosome anomalies
repro chromosome anomalies
- 1. CHROMOSOME CONCEPTS ANDCONDITIONS Dr H Bezuidenhout
- 2. • The classificationof genetic disorders • Introduction to congenital abnormalities and birth defects • Numerical and structural chromosomal disorders, including microdeletions • Cytogenetic and clinical discussion of Down’s syndrome, Edward, Patau and sex chromosomal disorders • Microdeletion syndromes - Prader-Willi, Angelman, Di George, Williams syndrome. • Cytogenetics: Use of karyotype and FISH
- 3. Classification of geneticdisorders • Chromosomal disorders • Copy number variants • Single gene disorders • Multi-factorial disorders • “Acquired” disorders • Unknown / idiopathic
- 4. Classification of geneticdisorders • Chromosomal disorders • Copy number variants (microdeletions / duplications) • Single gene disorders • Multi-factorial disorders • “Acquired” disorders • Unknown / idiopathic Chromosomal
- 5. Classification of geneticdisorders • Chromosomal disorders • Copy number variants (microdeletions / duplications) • Single gene disorders • Multi-factorial disorders • “Acquired” disorders • Unknown / idiopathic Microdeletion
- 6. Classification of geneticdisorders • Chromosomal disorders • Copy number variants (microdeletions / duplications) • Single gene disorders • Multi-factorial disorders • “Acquired” disorders • Unknown / idiopathic Single gene
- 7. Classification of geneticdisorders • Chromosomal disorders • Copy number variants (microdeletions / duplications) • Single gene disorders • Multi-factorial disorders • “Acquired” disorders • Unknown / idiopathic Multiple genes Environment
- 8. Classification of geneticdisorders • Chromosomal disorders • Copy number variants (microdeletions / duplications) • Single gene disorders • Multi-factorial disorders • “Acquired” disorders Prenatal (congenital) • Unknown / idiopathic
- 9. Classification of geneticdisorders • Chromosomal disorders • Copy number variants (microdeletions / duplications) • Single gene disorders • Multi-factorial disorders • “Acquired” disorders • Unknown / idiopathic
- 10. Classification of geneticdisorders • Chromosomal disorders: • Numerical • Structural • Mosaicism • Copy number variants (microdeletions / duplications) • Single gene disorders: • Autosomal (Dominant or Recessive) • X-linked (Dominant or Recessive) • Mitochondrial • Multifactorial disorders • “Acquired” disorders: • Prenatal (congenital) onset • Unknown / idiopathic
- 11. Congenital abnormalities/ birthdefects “ any abnormality of structure or function that is present, although not necessarily obvious, at the time of birth” • 2-3% of newborns have major congenital defect • cause may be genetic or related to the intra-uterine environment • MAJOR: lifelong defect with debilitating effect/death • MINOR: unusual morphologic defect without serious medical or cosmetic effect (14%) Single or multiple (>3 anomalies significant))
- 12. Dysmorphism • Dysmorphology– study of human malformations (“the study of abnormal form”) • Normal variation – (present in >1% individuals) • Dysmorphism – characteristics outside normal variation
- 13. Ploidy • Ploidyis the number of sets of chromosomes in the cell nucleus • Gamete has a single copy of each chromosome, HAPLOID N (N=23) • Normal human cell has 2 complete haploid sets, therefore DIPLOID (2N= 46)
- 15. 47,XYY • 1:1000male births • not APA effect • not dysmorphic • either incidental prenatal, postnatal • tall stature • Learning - mainstream school • behavioural problems – defiant type, • NOT associated with criminality • fertile, normal offspring
- 16.
- 17. Chromosomal abnormalities •Number OR Structure • Meiosis OR Mitosis • Meiosis (gametes formation) • Mitosis (cell division into 2 identical daughter cells)
- 18. Chromosomal abnormalities •Number OR Structure • Meiosis OR Mitosis Diploid 46 (2N) • Meiosis (gametes formation) Haploid 23 (N) • Mitosis (cell division into 2 identical daughter cells)
- 19. Chromosomal abnormalities •Number OR Structure • Meiosis OR Mitosis • Meiosis (gametes formation) • Mitosis (cell division into 2 identical daughter cells)
- 20. Chromosomal anomalies Numerical • Polyploidy – more than one pair of chromosomes , exact multiple of haploid (N) (N=23) eg. (3N=69) (4N=92) • Aneuploidy - extra copy/ absence of a chromosome eg. (47) (45) Structural • Translocations • Ring • Isochromosome • Inversion • Deletions • Duplications CNV • Microdeletions • Microduplications Mosaicism
- 21. Mosaicism • Individualwith 2 or more cell types originating from a single zygote • Different chromosome number (or structure) • Usually after conception, happens in embryo • Non-disjunction during mitosis in the zygote • 47,XX+21 [10] / 46,XX [20] • Unpredictable phenotype
- 22.
- 23. Mosaicism - Abnormalmitotic division in early development of the embryo
- 24. Translocation Exchange ofchromosomal material between two or more chromosomes Normal Balanced - no essential chromosome material lost - individual normal - carrier of balanced translocation
- 25. Translocation Unbalanced -extra chromosomal material and / or loss of chromosomal material - individual not normal Too much Too little
- 26. Balanced carrier –Unbalanced offspring Normal balanced carrier Abn MCA, development, growth meiosis Too much Too little
- 27. Chromosomal abnormalities Numerical • Polyploidy • Aneuploidy STRUCTURAL
- 28. Numerical –(Polyploidy) Triploidy 69,XXY; 69,XXX; 69,XYY (3N) • Miscarriages (2nd or 1st trimester) • Fetus: variable, growth, MCA (renal, cardiac, cns, sex), dysmorphism, assymmetry (mosaic), developmental delay • Paternal origin of extra set cause: Placental abnormality (partial molar) Gestational hypertension
- 30. Triploidy- Recurrence •Sporadic (random chance) • Low recurrence risk in next pregnancy • Molar pregnancy – at risk of developing choriocarcinoma (need follow-up)
- 31. Numerical -Aneuploidy • Autosomal aneuploidy o Down syndrome o Edwards syndrome o Patau syndrome • Sex chromosome aneuploidy o Turner syndrome o Klinefelter syndrome o 47,XYY
- 32. Down syndrome (extra21) Features • Hypotonia • Brachicephaly • Nuchal fold • Upslanting palpebral fissures • Epicanthic folds • Flat facial profile and flat nasal bridge • Low placed simple ears, overfolded helixes • Brachydactyly • Clinodactyly • Simian palmar crease • Sandal gap- wide space // toes 1 & 2
- 37. Down syndrome -Morbidity • IQ 25- 75 ( few over 50) • Cardiac (40%) • Recurrent infections esp respiratory • Thyroid • Opthalmology – cataracts, strabismus,myopia, nystagmus • Atlanto-axial instability • Hearing problems secondary CSOM • 2% risk leukemia (ALL,AML) • Transient Myeloproliferative Disorder • Duodenal atresia, Hirshsprung • Growth, obesity • Alzheimer type dementia
- 38. Down syndrome –Diagnosis 1:1000 births • Trisomy 21 47,XY,+21 95% • due to non-dysjunction • Translocation 46,XY,rob(14;21),+21 3% • Mosaic 47,XX,+21 / 46,XX 2%
- 39. Trisomy 21 DownSyndrome
- 40. Non-dysjunction • Failureof chromosomes to separate normally during cell division (meiosis) • Cause is unknown, ? random, ? maternal age • Result is aneuploidy
- 41. Translocation Down syndrome • 46,XY,rob(14;21),+21
- 42. Robertsonian translocation •Chromosomes 13, 14, 15, 21, 22 • Acrocentric have same genetic material on short arms (p) • Short arms (p) break off, long arms (q) fuse
- 44. Mosaic Down syndrome • 47,XY,+21[10] / 46,XY [20] mitosis
- 45. Down syndrome –Antenatal Diagnosis Screening • Ultrasound Markers (nuchal), abnormalities • Biochemical (from 9weeks) • Non-invasive testing Calculate specific risk (using age as well) Diagnostic Testing • Invasive testing (CVS, amniocentesis, cordocentesis)
- 47. Down syndrome –Antenatal Diagnosis Screening • Ultrasound Markers (nuchal), abnormalities • Biochemical (from 9weeks) • Non-invasive testing Calculate specific risk (using age as well) Diagnostic Antenatal Testing • Invasive testing (CVS, amniocentesis, cordocentesis)
- 48. Down Syndrome -Recurrence risk ~30% abort spontaneously after 12w Trisomy 21 • <35yr 1% • >35yr mat age risk + 1% Mosaic <1% Translocation increased RR if one parent carries a balanced translocation
- 50.
- 51. 14 21 NNN Down syndrome
- 52. Risks for ChromosomeAbnormalities at Term by Maternal Age Maternal Age at Term Risk for T21 Risk for any chr abn 15 1:1578 1:454 25 1:1351 1:475 30 1:909 1:384 35 1:384 1:178 36 1:307 1:148 37 1:242 1:122 38 1:189 1:104 39 1:146 1:80 40 1:112 1:62
- 53. Edward syndrome (extra18) • Head – prominent occiput, narrow bifrontal • Face - Low set pixie ears, small eyes, small nose,mouth,chin • Clenched hands, overlapping fingers, nail hypoplasia • Rockerbottom feet, short halluxes • Narrow hips • Genital • Short sternum • Cardiac, kidney, limb, CNS • Growth • Feeding Morbidity and mortality • “lethal” profound developmental impairment
- 58. Edward syndrome (extra18) • Head – prominent occiput, narrow bifrontal • Face - Low set pixie ears, small eyes, small nose,mouth,chin • Clenched hands, overlapping fingers, nail hypoplasia • Rockerbottom feet, short halluxes • Narrow hips • Genital • Short sternum • Cardiac, kidney, limb, CNS • Growth • Feeding Morbidity and mortality • “lethal” profound developmental impairment
- 59. Edward syndrome (extra18) 47,XX,+18 47,XY,+18 • 1/3 000 births • “lethal” • 95% spontaneous abortion • 50% die in 1st week of life • 5-10% survive 1st year Mosaic Not acrocentric/ not robertsonian translocation Etiology • Non-dysjunction • Maternal age effect
- 60. Edward Syndrome -Trisomy 18
- 61. Trisomy 18 –Recurrence risk • Low recurrence risk • ~1%
- 62. Patau syndrome (extra13) • Face - Hypo/hypertelorism (holoprosencephaly) Low set dysplastic ears Cleft lip and or palate • Polydactyly • Genital • Feet rockerbottom • Cardiac, renal, CNS • Cutis aplasia Morbidity and mortality “lethal”, profound developmental impairment
- 65. Patau syndrome (extra13) • Face - Hypo/hypertelorism (holoprosencephaly) Low set dysplastic ears Cleft lip and or palate • Polidactyly • Genital • Feet rockerbottom • Cardiac, renal, CNS • Cutis aplasia Morbidity and mortality “lethal”, profound developmental impairment
- 66. Patau syndrome -Trisomy 13 47,XY,+13; of 47,XX,+13 1/6 000 births • 50% die 1st month • 5% survive 6 months Mosaicism Translocasion 46,XX,rob(13;14) Etiology • 65% maternal non-dysjunction • Maternal age effect
- 67. Patau syndrome -Trisomy 13
- 68. Patau syndrome- Recurrencerisk • <1% if parents not translocation carrier • translocation carrier – RR as for Trisomy 21
- 69. Sex Chromosome aneuploidy • SCA - Presence of extra or absent sex chromosome (abn X) • Mosaic pattern • Incidence 1:400 males 1:650 • Turner syndrome • Klinefelter syndrome • Multiple X’s or Y’s (47,XXX 47,XYY 49,XXXXX)
- 70. Turner Syndrome Normalphenotype OR dysmorphic • Web neck, with low hairline (cystic hygroma) • Oedema of feet, hands • Shield chest, lowset wide nipples • Cubitus valgus Short stature (1.47m) Congenital anomalies (cardiac, renal) Specific Learning problems (non verbal skills) Gonadal dysgenesis/ amenorhee/ Infertility Systemic conditions Cancer risk (gonadoblastoma 45,X/ 46,XY)
- 74. Turner Syndrome Normalphenotype OR dysmorphic • Web neck, with low hairline (cystic hygroma) • Oedema of feet, hands • Shield chest, lowset wide nipples • Cubitus valgus Short stature (1.47m) Congenital anomalies (cardiac, renal) Specific Learning problems (non verbal skills) Gonadal dysgenesis/ amenorhee/ Infertility Systemic conditions Cancer risk (gonadoblastoma 45,X/ 46,XY)
- 75. Turner syndrome (cont) • Learning • Normal IQ (10-15 points below sib) • Non verbal skills • ADHD • Social adjustment • Delayed puberty/ amenorrhea (Rx Hormone) • Spontaneous pregnancy (0.5%) • Assisted pregnancy (donor ovum), increased morbidity and mortality
- 76. Turner syndrome •1 in 2500 live female births • 45,X and variants • Mosaic, count 30 cells • Structural X anomaly 45,X[10]/46,XX[20] 45X/46,XY 46,X,i(X) 45,X/46,X,r(X) • Antenatal – 99% TS conceptions loss, intrauterine lethality 14-40w of 65%
- 77.
- 78. Klinefelter syndrome •1:500 • Dx prenatal – incidental finding • postnatal – infertility work-up • Phenotype – not dysmorphic, tall • Learning problems (IQ average to low average) (91), language disorders 70% (verbal, conceptual), reading disabilities, executive function deficits • Behavioural problems • Puberty (hypergonadotrophic hypogonadism) (decreased testosterone) (testes involute in puberty) • Infertility • Gynecomastia (30%), other health risks as adults • Increased risk breast cancer
- 79.
- 80. Break ---- MockQuestion Groups 8 (4 in one row, with 4 in next row)
- 83. Mock Question 1: (a) Normal male karyotype (b) Robertsonian translocation carrier (c) Imprinting (d) Polyploidy (e) Unbalanced translocation (f) Normal female karyotype (g) Reciprocal translocation (h) None of the above Match the karyotype below to the correct letter above: (i) 45, X …….. (ii) 45,XX,rob(13;14) …….. (iii) 46,XX ……..
- 87. Chromosomal abnormalities Numerical • Polyploidy • Aneuploidy STRUCTURAL
- 88. Structural Abnormalitiesof chromosome structure • Part of a chromosome may be deleted • Extra piece of chromosomal material • Chromosomal material breaks and is swapped around • Translocations • Inversion • Ring • Deletions • Duplications CNV • Microdeletions • Microduplications
- 89. Translocation • Exchangeof chromosomal material between two or more chromosomes • 1:1000 live births • Most common structural chromosome abnormality in humans • One break in each chromosome, exchange of broken segments • Reciprocal (parts of chromosome) • Robertsonian (whole chromosome) If no essential chromosome material lost (BALANCED) (normal) increased chance of chromosomally unbalanced offspring
- 90.
- 91. Inversion • Ifno disruption of gene, may have no effect
- 92.
- 93.
- 94. CNV Microdeletions •Diagnosis – usually not visible on karyotype, FISH
- 95. Microdeletions • Examplesof syndromes • Prader-Willi 15q11 • Angelman 15q11 • Di-George 22q- • Williams 7q-
- 96. Prader Willi syndrome Baby: • Hypotonia • Long face, bitemporal narrowing • Downturned mouth corners • Almond shape eyes • Feeding problems Child: • Insatiable appetite • Small hands and feet • Short stature • Developmental delay, Intellectual disability, behavioural problems • Morbidity – Obesity, Diabetes
- 98. Prader Willi syndrome • 75 % microdeletion 15q11-12 • ~25% uniparental disomy • ~2% - “imprinting “ centre mutation • other chromosome 15 abnormality • Imprinting disorder
- 99. Genomic Imprinting “processby which certain genes are expressed in a specific parent-of-origin manner”
- 100. Genomic Imprinting •Not ALL genes, only some are genetically imprinted, “stamped”, during gamete production to silence them • Some genes are only expressed from the maternal or paternal allele. There is only 1 copy “active” • For imprinted genes - Only 1 copy of gene expressed normally (“active”) and therefore any loss due to mutation/deleted/silenced will have an effect
- 101. Genomic Imprinting •Reprogramming - process involve erase previous parent pattern, imprint new pattern (switch off, or leave on), maintain in mitosis • Imprinted alleles are silenced such that the genes are expressed only from the non-imprinted allele • No altering of genetic sequence • Independent of the classical mendelian inheritance • Happens in germline (gonads) For some genes parent of origin is important
- 102. Dad Mom NAbn Abn
- 103. Dad Mom NAbn Abn
- 104. Dad Meiosis PraderWilli Child
- 105. Dad PraderWilli Deletion 15q11-12 No paternal Meiosis
- 106. Mom Imprinting N PraderWilli Offspring Meiosis Uniparental Disomy Trisomy rescue
- 107. Prader Willi -Recurrence risk • RR: usually low (de novo) • Only if other chr 15 abnormality, imprinting centre
- 108. Angelman syndrome Face:wide mouth, wide-spaced teeth, prognathia (protruding lower jaw) Hypopigmented skin, light hair and eye colour (compared to family) Microcephaly Severe developmental delay (speech) Ataxia, uplifted, flexed arm position especially during ambulation (puppet) Seizures Tongue thrusting; suck/swallowing disorders, Feeding problems during infancy, Excessive chewing/mouthing behaviours Happy demeanor (laugh inappropriately) Attraction to/fascination with water
- 110.
- 111. Angelman syndrome •70% 15q11 deletion (maternal) • 5% Uniparental disomy (paternal) • Imprinting disorder (opposite to Prader Willi) Recurrence risk • Low if de novo deletions
- 112. Di George syndrome(22q deletion) • Dysmorphism • Developmental delays • Congenital anomalies - cleft palate/ soft palate dysfunction, cardiac, renal, absent thymus, spine • Immune deficiency • Hypocalcemia • Hearing loss • Behavioral and psychiatric disorders; • Growth deficiency • Frequent upper respiratory illnesses and ear infections; • GERD
- 113. Di George syndrome(22q deletion)
- 114. Di George syndrome(22q deletion) • 22q11.2 deletion Recurrence risk • De novo (94%) - low • 6% familial – offer parental studies (RR 50% if parent has deletion) (variability in expression)
- 115. Williams syndrome •Dysmorphism – prominent lips, wide mouth, hoarse voice, periorbital fullness, dental, joint hypermobility • Congenital anomalies – cardiac, renal • Moderate to severe learning difficulties, verbal abilities superior to visuo-spatial and motor skills • Socially disinhibited
- 116.
- 117. Williams syndrome •7q11.23 Deletion Recurrence risk • Usually low (de novo)
- 118. Summary Numerical chromosomeabn • Autosomes (lethal/ miscarriage) (MCA, development, growth) • Sex chromosome (Mild or no dysmorphism, affect secondary sexual characteristics, fertility) Structural chromosome abn • Balanced (No dysmorphism, no abnormalities, infertility, miscarriages, at risk of unbalanced offspring)
- 119. Summary • Meiosisvs mitosis gametes formation, diploid 2 N haploid N cell division into 2 identical daughter cells, diploid 2N diploid 2N • Mosaicism Presence of 2 or more cell types originating from a single zygote Non-dysjunction during mitosis in the zygote • Non-dysjunction Failure of chromosomes to separate normally during cell division (meiosis) • Triploidy vs aneuploidy whole extra haploid set vs 1 or more extra/loss chromosome/s • Imprinting process by which certain genes are expressed in a specific parent-of-origin manner