Genetics 1

Question 1

What two possibilities are considered when looking for abnormalities in babies

Answer 1

Chromosomal and congenital abnormalities

Question 2

What are the statistics associated with congenital abnormalities

Answer 2

1 : 50 newborns

20-25% of all deaths before age 10

Genetic factors contribute to about 40%

Question 3

What are the two categories of congenital abnormalities

Answer 3

Single and multiple

Question 4

What are the single congenital abnormalities

Answer 4

Malformation
Disruption
Deformation
Dysplasia

Question 5

What are the multiple congenital abnormalities

Answer 5

Sequence
Syndrome
Association

Question 6

What is malformation

Answer 6

A morphologic defect of an organ, part of an organ, or larger region of the body resulting from an intrinsically abnormal developmental process- congenital heart defects

Question 7

What is disruption

Answer 7

A morphologic defect of an organ, part of an organ, or larger region of the body resulting from the extrinsic breakdown of, or interference with, an originally normal developmental process
Caused by ischaemia, infection, trauma. Not genetic, but genetic factors can predispose
Development starts normally

Question 8

What is deformation

Answer 8

Abnormal form, shape or position of a part of the body caused by mechanical forces- club foot
Potentially reversible
Occurs late in pregnancy and has a good prognosis as the underlying structure is normal

Question 9

What is dysplasia

Answer 9

An abnormal organisation of cells into tissue(s) and its morphologic results(s)
Thanatophric dysplasi
Bowed long bones, narrow thorax, large skull
1:60,000
Single gene (FGFR3)
High recurrence risk for siblings/ offspring

Question 10

What is a sequence

Answer 10

A pattern of multiple anomalies derived from a single known or presumed prior anomaly or mechanical factor

e.g., Potter sequence

Question 11

What is a syndrome

Answer 11

Multiple anomalies thought to be pathogenetically related and not representing a sequence

e.g., Down syndrome

Question 12

What is association

Answer 12

Association:
A nonrandom occurrence in two or more individuals of multiple congenital abnormalities not known to be a polytopic defect, sequence, or syndrome
e.g., VACTERL association
Vertebral anomalies
Anal atresia
Cardiac defects
Tracheoesophageal fistula 
Esophageal atresia
Renal/Radial anomalies 
Limb defects

Question 13

What are the levels of organisation of the genome

Answer 13

DNA
Gene
Chromosome
Genome

Question 14

What chromosomes do you inherit from each parent

Answer 14

From one parent you inherit:
22 autosomes (chr. 1-22)
1 sex chromosome (X or Y)
This is the haploid number (23)

Question 15

What is chromosome banding

Answer 15

Analyse sample of dividing cells under the microscope
Current protocols leave sister chromatids pressed tightly together- hence cytogeneticists rely on the banding pattern to identify chromosomes. The usual method is G-banding, which subjects the chromosomes to a brief digestion with trypsin-followed by staining with Gimesa stain.
Each chromosome has a specific banding pattern.

Question 16

What are the other types of chromosome banding

Answer 16

R-banding - reversed pattern of light and dark bands, useful for checking chromosome ends.
C- banding- stain the centromeres or the short arms of the acrocentric chromosomes ( silver staining).

Question 17

How are bands counted

Answer 17

Outwards from the centromere.

Question 18

Why are sub-bands now present

Answer 18

Improvement in techniques has allowed us to see the bands in a higher resolution. For example, cells can be harvested before the chromosomes become maximally contracted in metaphase. In these highly extended chromosomes, we can see sub-bands and sub-sub bands. However in longer chromosomes, they can become tangled, limiting resolution, hence molecular tests are required.

Question 19

How is each arm identified

Answer 19

Long arm- q

Short arm - p

Question 20

What does acrocentric mean

Answer 20

A chromosome that has its centromere close to one end- 13,14,15,21 and 22

Question 21

What is a centromere

Answer 21

The position on the chromosome in which sister chromatids are joined, and where the spindle fibres attach during cell division.

Question 22

What does metacentric mean

Answer 22

A chromosome that has its centromeres in the middle- 3 and 20

Question 23

What is monosomy

Answer 23

Having 1 copy of a particular chromosome, but 2 of all the others.

Question 24

What is robertsonian translocation

Answer 24

A special type of translocation in which two acrocentric chromosomes are joined close to their centromeres. Function as a single chromosome in mitosis- small acentric fragment comprising the two distal short arms is lost.

Question 25

What are sister chromatids

Answer 25

The two chromatids of a chromosome as seen in a dividing cell. Sister chromatids are copies of each other, made during the preceding round of DNA replication.

Question 26

What does submetacentric mean

Answer 26

A chromosome that has a long arm and a short arm.

Question 27

What is a translocation

Answer 27

A structural abnormality in which two chromosomes are non-homologous segments

Question 28

What is triploidy

Answer 28

Having three complete sets of chromosomes

Question 29

What are the three types of chromosomal abnormality

Answer 29

Structural: translocations, deletions, insertions, etc. Numerical: aneuploidy = loss or gain Mosaicism: different cell lineages

Question 30

Statistics of chromosomal abnormalities

Answer 30

Chromosome abnormalities are present in: 60% of early spontaneous miscarriages 4-5% of stillbirths 7.5% of all conceptions, 0.6% of live births

Question 31

What is mosaicism caused by

Answer 31

Mosaicism is where there is more than one cell lineage in a tissue, i.e. some cells might have an extra chromosome 21 and others have the normal number (see later). This is due to mitotic non-disjunction. How early it happens determines how many tissues and which tissues the genetic abnormality might affect. A late non-disjunction event may have no visible effect whereas an early one might have severe effects.

Question 32

What is a balanced translocation

Answer 32

No loss or gain of genetic material, genes just present on different chromosomes, usually has no effect- cells can still divide as normal provided that they have a single centromere and proper telomeres.

Question 33

Consequences of an unbalanced translocation

Answer 33

Gene disrupted, toxic gene fusion product- seen in leukaemia (Philadelphia chromosome). However robertsonian translocatons are regarded as balanced even though two short arms have been lost- encode similar sequences of RNA anyway.

Question 34

What are the 4 types of structural abnormalities

Answer 34

Deletion, ring, duplication, translocation

Question 35

What is aneuploidy

Answer 35

The loss or gain of one or more chromosomes

Question 36

Which trisomy is most common

Answer 36

16, but fatal in utero- second most common cause of miscarriage.

Question 37

What does trisomy 13 cause

Answer 37

: Patau syndrome Heart defects (septal defects, patent ductus arteriosus) Holoprosencephaly (cleft lip/palate, hypotelorism) Mental retardation

Question 38

What does trisomy 18 cause

Answer 38

Edwards syndrome Heart defects (septal defects, patent ductus arteriosus) Kidney malformation (horseshoe kidney) Digestive tract defects (omphalocele, oesophageal atresia) Mental retardation

Question 39

Symptoms of down syndrome

Answer 39

New-born - hypotonia, lethargy, excess nuchal skin Craniofacial - macroglossia, small ears, epicanthic folds, sloping palpebral fissures, Brush field spots Limbs - single palmar crease, wide gap between first and second toes (“sandal gap”) Cardiac - septal defects, atrioventricular canal Other - short stature, duodenal atresia

Question 40

What is trisomy 21 caused by

Answer 40

translocations, mosaicism, non-dysjunction event in meiosis I or II- forming 2 disomic gametes and 2 nullsomic gametes- die.

Question 41

What is mosaicism caused by

Answer 41

Caused by mitotic non-disjunction Children less severely affected One trisomy- 1 monosomy

Question 42

Why may trisomies cause disease

Answer 42

Transcription factors / regulatory elements? Cell surface receptors / transporters? Subunits of multimeric proteins?

Question 43

Potential causes of monosomy X- Turner's syndrome

Answer 43

80% loss of X or Y in paternal meiosis | 20% other causes (ring chromosome, single arm deletion, mosaicism)

Question 44

Symptoms of turner's syndrome

Answer 44

``` Prenatal: Generalised oedema Swelling in neck Newborn/child: Oedomatous hands/feet Webbed neck Low-set ears Low posterior hairline Broad chest Short 4th metacarpals Aortic defects (valve defects, coarctation) Urinary defects (e.g., horseshoe kidney) Adults, complications: Short stature (avg. 145cm if untreated) Ovarian failure  primary amenorrhoea and infertility Diabetes Hypothyroidism Normal intelligence ```

Question 45

What are the treatments available for Turner's syndrome

Answer 45

Growth hormone | Oestrogen replacement

Question 46

Why does monosomy X cause turner's syndrome

Answer 46

Monosomy X results has an effect because a few genes on the X are known to escape X-inactivation (and so need both copies for full expression) and the parental origin of the X is important (imprinting).

Question 47

What is Klinefelter's syndrome

Answer 47

``` Phenotypically male 1:1000 male live births Learning disability (IQ 80-90) Taller than average (long lower limbs) Gynaecomastia Infertility Risk of leg ulcers, osteoporosis and breast carcinoma in adult life X chromosome can be from either parent Rare variants: 48,XXXY and 49,XXXXY ```

Question 48

What is the importance of dosage compensation

Answer 48

Ensures equivalent gene expression in both sexes

Question 49

How is dosage compensation achieved

Answer 49

Mechanisms: Random inactivation of a single X chromosome in females (most mammals) – lyonization, formation of Barr bodies histone tail modifications, DNA methylation patterns, and reorganization of large-scale chromatin structure encoded by the X-ist gene

Question 50

How is it possible to be chromosomally one gender and phenotypically the opposite

Answer 50

Recombination of SRY ( normally on Y onto X) | Causes development of female sexual characteristics

Question 51

What are genomic disorders

Answer 51

Caused by the loss/gain of DNA Deletion syndromes Di George syndrome Duplication syndromes Charcot-Marie-Tooth disease type 1A May not be visible in the karyotype Micro-deletion syndromes

Question 52

What is Di George syndrome

Answer 52

Micro-deletion 22q11.2 (30-50 genes, including TBX1) Diagnostic features: Cardiac anomalies (interrupted aortic arch, ToF) Abnormal facies (low-set ears, widely-spaced eyes) Thymic hypoplasia Cleft palate Hypocalcaemia (parathyroid hypoplasia) TBX1 is the T-box 1 gene that codes for a transcription factor involved in the regulation of many developmental processes

Question 53

What is Charcot-Marie-Tooth disease type 1A

Answer 53

Micro-duplication of 17p11.2 (incl. PMP22) Demyelinating peripheral neuropathy in adolescence Diagnostic features: Foot drop Distal muscle wasting/weakness Foot deformities (pes cavus = high arch) Absent reflexes Lack of sensation in upper/lower limbs Slow nerve conduction velocity Treatment: Physiotherapy, corrective surgery PMP22 is the Peripheral Myelin Protein 22 gene that encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system.

Question 54

Non-disjunction in meiosis I and II

Answer 54

I- Chromosomes fail to separate in anaphase | II- Sister chromatids fail to separate in anaphase.