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

Classification of genetic disorders

• Chromosomal disorders

• Copy number variants (microdeletions / duplications)

• Single gene disorders

• Multi-factorial disorders

• “Acquired” disorders

• Unknown / idiopathicChromosomal

Classification of genetic disorders

• Chromosomal disorders

• Copy number variants (microdeletions / duplications)

• Single gene disorders

• Multi-factorial disorders

• “Acquired” disorders

• Unknown / idiopathic

Microdeletion

Classification of genetic disorders

• Chromosomal disorders

• Copy number variants (microdeletions / duplications)

• Single gene disorders

• Multi-factorial disorders

• “Acquired” disorders

• Unknown / idiopathic

Single gene

Classification of genetic disorders

• Chromosomal disorders

• Copy number variants (microdeletions / duplications)

• Single gene disorders

• Multi-factorial disorders

• “Acquired” disorders

• Unknown / idiopathic

Multiple genes

Environment

Classification of genetic disorders

• Chromosomal disorders

• Copy number variants (microdeletions / duplications)

• Single gene disorders

• Multi-factorial disorders

• “Acquired” disordersPrenatal (congenital)

• Unknown / idiopathic

Classification of genetic disorders

• Chromosomal disorders

• Copy number variants (microdeletions / duplications)

• Single gene disorders

• Multi-factorial disorders

• “Acquired” disorders

• Unknown / idiopathic

Classification of genetic disorders

• 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

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

Chromosomes

46,XX 46,XY

Chromosomal abnormalities

• Number OR Structure

• Meiosis OR Mitosis

• Meiosis (gametes formation)

• Mitosis (cell division into 2 identical daughter cells)

Chromosomal abnormalities

• Number OR Structure

• Meiosis OR Mitosis

• Meiosis (gametes formation)

• Mitosis (cell division into 2 identical daughter cells)

Diploid 46 (2N)

Haploid 23 (N)

Chromosomal abnormalities

• Number OR Structure

• Meiosis OR Mitosis

• Meiosis (gametes formation)

• 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

47,XX,+2146,XX

46,XX

Mosaicism - Abnormal mitotic division in early

development of the embryo

TranslocationExchange of chromosomal material between two or more chromosomes

Balanced - no essential chromosome material lost - individual normal- carrier of balanced translocation

Normal

Translocation

Unbalanced - extra chromosomal material and / or loss

of chromosomal material

- individual not normal

Too much

Too little

Balanced carrier – Unbalanced offspring

Abn

MCA, development, growth

Normal balanced carrier

meiosis

Too much

Too little

Chromosomal abnormalities

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%

Trisomy 21 Down Syndrome

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

Parent Balanced translocation

1421

NN NDown

syndrome

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)

• 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

Edward Syndrome - Trisomy 18

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

Morbidity and mortality

“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

Morbidity and mortality

“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 - Trisomy 13

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

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%

Turner Syndrome 45,X

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

Klinefelter syndrome 47,XXY

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 ……..

Chromosomal abnormalities

Numerical

• Polyploidy

• Aneuploidy

STRUCTURAL

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

Translocation balanced

Inversion

• If no disruption of gene, may have no effect

Ring chromosome

Deletion

5p deletion

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

DadMom

N AbnAbn

DadMom

N AbnAbn

Dad

Prader Willi

Meiosis

Child

Dad

Prader Willi

Deletion

15q11-12

No paternalMeiosis

Mom

N

Imprinting

Prader Willi

Offsp

ring

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

Di George syndrome (22q deletion)

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)

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

syndrome

Williams syndrome

• 7q11.23 Deletion

Recurrence risk

• Usually low (de novo)

SummaryNumerical 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

• MosaicismPresence of 2 or more cell types originating from a single zygote

Non-dysjunction during mitosis in the zygote

• Non-dysjunctionFailure 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