repro chromosome anomalies

CHROMOSOME CONCEPTS
AND CONDITIONS
Dr H Bezuidenhout

• The classification of 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

Classification of genetic disorders
• Chromosomal disorders
• Copy number variants
• Single gene disorders
• Multi-factorial disorders
• “Acquired” disorders
• Unknown / idiopathic

• Copy number variants (microdeletions /
duplications)
Chromosomal

duplications)
Microdeletion

duplications)
Single gene

duplications)
Multiple genes
Environment

duplications)
Prenatal (congenital)

duplications)

• 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

Congenital abnormalities/ birth defects
“ 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))

Dysmorphism
• Dysmorphology – study of human malformations
(“the study of abnormal form”)
• Normal variation – (present in >1% individuals)
• Dysmorphism – characteristics outside normal
variation

Ploidy
• Ploidy is 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)

47,XYY
• 1:1000 male 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

Chromosomal abnormalities
• Number OR Structure
• Meiosis OR Mitosis
• Meiosis (gametes formation)
• Mitosis (cell division into 2 identical daughter cells)

• Number OR Structure
• Meiosis OR Mitosis
Diploid 46 (2N)
• Meiosis (gametes formation)
Haploid 23 (N)
• Mitosis (cell division into 2 identical daughter cells)

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

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

Mosaicism - Abnormal mitotic division in early
development of the embryo

Translocation
Exchange of chromosomal material between two or more
chromosomes
Normal
Balanced - no essential chromosome material lost
- individual normal
- carrier of balanced translocation

Translocation
Unbalanced - extra chromosomal material and / or loss
of chromosomal material
- individual not normal
Too much
Too little

Balanced carrier – Unbalanced offspring
Normal balanced carrier
Abn
MCA, development, growth
meiosis
Too much
Too little

Numerical
• Polyploidy
• Aneuploidy
STRUCTURAL

 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

Triploidy- Recurrence
• Sporadic (random chance)
• Low recurrence risk in next pregnancy
• Molar pregnancy – at risk of developing
choriocarcinoma (need follow-up)

 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

Down syndrome (extra 21)
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

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

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%

Non-dysjunction
• Failure of chromosomes to separate normally
during cell division (meiosis)
• Cause is unknown, ? random, ? maternal age
• Result is aneuploidy

Translocation Down syndrome
• 46,XY,rob(14;21),+21

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

Mosaic Down syndrome
• 47,XY,+21[10] / 46,XY [20]
mitosis

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)

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)

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

Risks for Chromosome Abnormalities 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

Edward syndrome (extra 18)
• 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

Edward syndrome (extra 18)
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

Trisomy 18 – Recurrence risk
• Low recurrence risk
• ~1%

Patau syndrome (extra 13)
• Face - Hypo/hypertelorism (holoprosencephaly)
Low set dysplastic ears
Cleft lip and or palate
• Polydactyly
• Genital
• Feet rockerbottom
• Cardiac, renal, CNS
• Cutis aplasia
“lethal”, profound developmental impairment

Patau syndrome (extra 13)
• Face - Hypo/hypertelorism (holoprosencephaly)
Low set dysplastic ears
Cleft lip and or palate
• Polidactyly
• Genital
• Feet rockerbottom
• Cardiac, renal, CNS
• Cutis aplasia
“lethal”, profound developmental impairment

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

Patau syndrome- Recurrence risk
• <1% if parents not translocation carrier
• translocation carrier – RR as for Trisomy 21

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)

Turner Syndrome
Normal phenotype 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)

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

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%

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

Break ---- Mock Question
Groups 8 (4 in one row, with 4 in next row)

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 ……..

 Structural
Abnormalities of 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

Translocation
• Exchange of 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

Inversion
• If no disruption of gene, may have no effect

CNV Microdeletions
• Diagnosis – usually not visible on karyotype,
FISH

Microdeletions
• Examples of syndromes
• Prader-Willi 15q11
• Angelman 15q11
• Di-George 22q-
• Williams 7q-

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

Prader Willi syndrome
• 75 % microdeletion 15q11-12
• ~25% uniparental disomy
• ~2% - “imprinting “ centre mutation
• other chromosome 15 abnormality
• Imprinting disorder

Genomic Imprinting
“process by which certain genes are expressed in a
specific parent-of-origin manner”

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

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

Dad
Meiosis
PraderWilli
Child

Dad
PraderWilli
Deletion
15q11-12
No paternal
Meiosis

Mom
Imprinting
N
PraderWilli
Offspring
Meiosis
Uniparental Disomy
Trisomy rescue

Prader Willi - Recurrence risk
• RR: usually low (de novo)
• Only if other chr 15 abnormality, imprinting centre

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

https://www.youtube.com/watch?v=Q8eaYdF6x3A

Angelman syndrome
• 70% 15q11 deletion (maternal)
• 5% Uniparental disomy (paternal)
• Imprinting disorder (opposite to Prader Willi)
Recurrence risk
• Low if de novo deletions

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

• 22q11.2 deletion
Recurrence risk
• De novo (94%) - low
• 6% familial – offer parental studies (RR 50% if
parent has deletion) (variability in expression)

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

Williams syndrome
• 7q11.23 Deletion
Recurrence risk
• Usually low (de novo)

Summary
Numerical chromosome abn
• 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)

Summary
• Meiosis vs 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

repro chromosome anomalies

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