Chromosomes and Karyotype

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Acquired Chromosomal Abnormalities

arise during embryogenesis in only a subset of cells (mosaics)

Constitutional Chromosomal Abnormalities

found in each cell of the body

Causes of Chromosome Abnormality | Anaphase Lag

• an abnormal division in which one chromosome fails to migrate to the pole of the spindle

• the lagging chromosome is often excluded from the nuclei of the daughter cells and forms a micronucleus, which is degraded

Results in → euploidy (normal) and monosomy

Causes of Chromosome Abnormality | Misegregation (Non Disjunction) 

failure of homologous chromosomes (meiosis I) or sister chromatids (meiosis II) to separate

Non-disjunction | Meiosis I Errors

• all gametes are abnormal

• 50% carry both copies of the chromosome (trisomy, non-identical)

• 50% without either copies (monosomy)

Non-disjunction | Meiosis II Errors

• 50% gametes abnormal

• 1 with an extra chromosome copy (trisomy, identical) and 1 without (monosomy)

Anaphase vs Non-disjunction

Causes of Chromosome Abnormality | Meiotic Failure (A general Term)

• complete nondisjunction

• cells fail to separate (failed cytokinesis) in mitosis or meiosis

Causes of Chromosome Abnormality | Dispermy

simultaneous fertilisation of a haploid egg by 2 haploid sperm → triploidy

Causes of Chromosome Abnormality | Incorrect DNA Repair 

occurs (typically) when there is a  double-stranded break → DNA fragment is easily misplaced

Incorrect DNA Repair | Inversion → Paracentric Inversion

a segment of a single chromosome's arm breaks, flips 180 degrees, and reattaches, but without involving the centromere.

May not involve → loss or gain of chromosomal information 

Incorrect DNA Repair | Inversion → Pericentric Inversion

a segment of a chromosome breaks on either side of the centromere, flips 180 degrees, and then reattaches in reverse order, including the centromere itself

Do inversion always cause abnormality?

no, if the breakpoints of the inversion do not disrupt genes

How does the replication of inverted gene cause inversions?

chromosomes form a hairpin loop for crossing over of prophase → may lose or gain genes

Incorrect DNA Repair | Translocation

movement of genetic material to another nonhomologous chromosome

may not include → loss or gain chromosomal material

Incorrect DNA Repair | Translocation → Insertional Translocation

Where gene segments from one nonhomologus chromosome is insert to another nonhomologus with no reciprocation. Only one chromosome exchanges a gene segment. 

Incorrect DNA Repair | Translocation → Reciprocal Inversion

Where gene segment is exchanged between nonhomologous  chromosomes. They both exchanged gene segments with each other. 

Robertsonian Translocation

• centric fusions of acrocentric chromosomes → 2 acentric + 1 dicentric

• no net gain or loss of genetic material ∴ normal phenotype (balanced)

• increased risk for fetal abnormalities or miscarriage

Robertsonian Translocation | 2 normal split from qq and pp

DRAW IT

Robertsonian Translocation | normal + qq split from normal and pp?

DRAW IT

Incorrect DNA Repair | Deletion

• can be large or small

• size roughly correlates with the severity of the abnormality

Incorrect DNA Repair | Duplication

fragment of one deletion can bind with homologous partner → duplication

Ring Chromosomes 

• when telomeres are lost, and sticky chromosome ends fuse

What determines how affected an individual is?

the genes lost (symptomatic if genes are lost or disrupted)

What Each Abnormality Results in

Karyotype Disorders | Can Arise via  Non-disjunction and Robertsonians 

• trisomy 13

• trisomy 18

• trisomy 21

• monosomy X

Aneuploidy

addition/ loss of chromosomes (or parts) from the normal (euploid) set of 23

→ Inherited via meiotic errors furing gametogenesis 

caused via non-disjunciton

commonly as a trisonomy, rarely a monosomy 

Embryonically lethal in chromosomes → 10, 15, 16

Suriviable in chromosomes → 13, 18, 21 → because these are small chromosomes with less genes 

Possessing One chromosome is lethal but why can males have XY

• all females are mosaic

• normal cell development and function only require 1 X chromosome

• early in development, XX cells randomly deactivate one X (by XIST gene)

• the inactive X becomes hyper-condensed → Barr-body (heterochromatin)

Polyploidy

presence of whole sets of chromosomes in excess of the normal (euploid) set of 23

1. complete nondisjunction

2. cells fail to separate (failed cytokinesis) in mitosis or meiosis

3. dispermy

what % of early miscarriages show an abnormal karyotype

what is parent-of-origin imprinting?

phenomenon where gene expression depends on inheritance from biological father or mother

what is uniparental disomy?

inheritance of 2 chromosomes or chromosome parts from the same parent

Requires 

1. simultaneous non-disjunction in the same chromosomes in both egg and sperm

OR 

2. Trisomy followed by chromosome loss 

how can you tell how early an error occurred in an mosaic?

one with more cells (an earlier cell was affected so it has duplicated more)

what technology is used to detect many micro-deletions?

FISH (detects the presence or absence of specific genes on chromosomes by hybridisation)

why does ectodermal dysplasia present with patterned skin?

gene controlling ectodermal dysplasia are located on the X chromosome and turned off in some areas by X chromosome inactivation

Ectoderm Dysplasia | where is skin normal vs pink with no sweat glands?

1. Normal → where the X chromosome bearing the defective gene has been deactivated

2. Pink → where the X chromosome bearing the normal gene has been deactivated

what defect causes Hereditary Motor and Sensory Neuropathy?

duplication of 17p11.2 gene

what defect causes Charcot-Marie Tooth disease?

duplication of PMP22 gene

what defect causes William's Syndrome? consequence?

1. DNA loss around the 7q11.23 region

2. Consequences → vasculature disorder due to the loss of the elastin gene

Ring Chromosome 22 |

• cognitive impairment

• hypotonia (muscle weakness)

• lack of coordination

what causes Prader-Willi syndrome?

1. loss of paternal 15q11-13 region

Prader-Willi Syndrome | Clinical Features 

• chronic feeling of hunger → hyperphagia

• life-threatening obesity

Prader-Willi Syndrome | Clinical Features 

• chronic feeling of hunger → hyperphagia

• life-threatening obesity

Prader-Willi and Angelman’s Syndrome

Prader-Willi

1. deletion of paternal gene

2. maternal uniparental disomy

3. methylation defect (paternal gene switched off)

Angelman’s

1. deletion of maternal gene

2. paternal uniparental disomy

3. methylation defect (maternal gene switched off)

Balanced Translocation 

Common Features (#8)
Robertsonian translocation
Increased risk of Down’s
syndrome

45,X_ der(14;21)(q10;q10)

Classic Down Syndrome  | Trisomy 21

Flat Facial Features 

Increased gap between 1st and 2nd toe 

Increased nuchal fold

47,X_,+21

Cri Du Chat

Cat-like cry 

Down-slanted palpebral fissures 

46,X_,del(5)(p15.3)

Diplo-Y

Poor Coordination

Prominent glabella

Increased length vs breadth

→ Ears

→ Hands

→ Fingers

→ Feet 

→ Toes 

47,XYY

Edward Syndrome | Trisomy 18 

Short Sternum

Clenched hands with overlapping fingers

rocker-bottom-feet 

47,X_,+18

Klinefelter Syndrome

gynecomastia

Hypogonadism 

Hypospadias

Hypogenitalism  

 

47,XXY

Affected Sex | male

Patau Syndrome | Trisomy 13

Microphthalmia

Cutis aplasia of the scalp

holoprosencephaly

Polydactyly

47,X_,+13

Translocation Down Syndrome

Flat facial profile
Increased nuchal fold.

Increased gap between 1st
& 2nd toe.
Single Palmar Crease

Triple X

Development is almost
normal.
Clinodactyly

Tendency for back
problems

47,XXX

Triploidy

Large placenta w/
hydatidiform changes

Low nasal bridge

Syndactyly of the 3rd & 4th
fingers

69,X_ _

Turners Syndrome

Pterygium colli deformity
Low posterior hairline
Broad chest w/ widely
spaced nipples

affected sex = females 

45,X

Wolf-Hirschorn Syndrome

Broad or beaked nose
Preauricular tag/pit → small hole in front of the upper ear, located just between the face and the cartilage of the ear rim

46, X_, del(4)(p16.3)

Jacobsen Syndrome

Broad nasal bridge
Macrocephaly
Trigonocephaly
Paris-Trousseau syndrome → which is a disorder of
platelets, which are
necessary for blood
clotting.

46,X_,del(11q)

Fragile X Syndrome

Prominent jaw and
forehead
Unusually flexible fingers
Flat feet
Males can display
macroorchidism after
puberty.

46,X_, fra(X)(q27.3)

Klinefelter Syndrome | Aneuploidy is usually fatal why no death here?…

X-chromosome inactivation, turns off all but one X chromosome per cell ∴ the ill effects of any extra chromosomes are reduced