Genetics 1- Mrs. Jones' First Consultation

Question 1

What is the prevelance and mortality of Congenital Abnormalities

Answer 1

Congenital abnormalities are apparent in birth in 1 in 50 of all newborn infants.

Responsible for 20-25% of all deaths during the perinatal period (number of weeks immediately before and after birth) and childhood up to the age of 10 years.

Genetic factors contribute to 40% of all genetic abnormalities.

Question 2

What are the 8 types of Classification of Congenital Abnormalities or Birth Defects

Answer 2

Malformation

Disruption

Deformation

Sequence

Syndrome

Dysplasia

Association

Dysmorphism

Question 3

Describe malformation

Answer 3

Primary structural defect e.g. atrial septal defects, cleft lip

Usually involves single organ showing multifactorial inheritance.

NOTE: Multifactorial Inheritance - many factors are involved in causing the birth defect. Factors are both genetic and environmental.

Question 4

Describe Disruption

Answer 4

Secondary abnormal structure of an organ or tissue e.g. amniotic band causing digital amputation (when the amniotic band wraps around a digit, restricting the blood flow and leading to amputation)

Caused by ischaemia, infection and trauma. It is NOT genetic but genetic factors can predispose.

Question 5

Describe Deformation.

Answer 5

Abnormal mechanical force distorting a structure e.g. club foot, hip dislocation

Occurs late in pregnancy and has a good prognosis because the underlying structure is normal.

Question 6

Describe Syndrome

Answer 6

Consistent pattern of abnormalities with a specific underlying cause e.g. Down Syndrome

This includes chromosomal abnormalities

Question 7

Describe Dysplasia

Answer 7

Abnormal organisation of cells into tissue e.g. thanatophoric dysplasia

Caused by a single gene defect

High recurrence risk for siblings/offspring

Short flat bones, small thorax, large head

Question 8

Describe Sequence

Answer 8

Multiple abnormalities initiated by a primary factor e.g. reduced amniotic fluid leads to Potter Sequence

Could have a genetic component as the initial factor.

Caused by Oligohydramnios - reduced volume of amniotic fluid due to failure to produce urine.

Question 9

Describe Association

Answer 9

Non-random occurrence of abnormalities NOT explained by syndrome.

Cause is typically unknown.

E.g. VACTERL association - Vertebral, Anal, Cardiac, Tracheo-Oesophagal, Renal, Limb

Question 10

What are the three types of chromosome abnormalities

Answer 10

Numerical - ANEUPLOIDY - loss or gain of chromosomes

Structural - translocations, deletions, insertions, inversions, rings (ends join together)

Mosaicism - different cell lineages do not contain identical chromosomes

Question 11

What is Autosomal Aneuploidy

Answer 11

Definition: Numerical abnormalities involving the loss or gain of one or more chromosomes. 3 types

Monosomy - loss of a single chromosome - almost always lethal

Trisomy - gain of one chromosome - can be tolerated

Tetrasomy - gain of two chromosomes - can be tolerated

Question 12

What are Partial Aneuploidy (TRANSLOCATIONS)

Answer 12

When part of the chromosome breaks off and joins its homologous chromosome

There could be translocations of certain parts of the chromosomes.

NORMAL - when no translocation takes place

BALANCED - when there is a straight switch of the sections of DNA - no genetic material lost

UNBALANCED - when part of the chromosome is lost - GENETIC MATERIAL IS LOST - if an important gene is lost, it could result in a non-viable embryo.

Question 13

What is the prevelance of down syndrome

How do the clinical features present in the new born period, craniofacial limbs and cardiac

What are the three causes

Answer 13

approx. 1 in 700 births
Strong association between incidence and maternal age (particularly above the age of 35)

Clinical Features of Down Syndrome
Newborn period - severe hypotonia, sleepy, excess nuchal skin (back of the neck) - can be diagnosed via ultrasound.

Craniofacial - macroglossia (large tongue), small ears, epicanthic folds (eye folds), upward sloping palpebral fissues (eye folds), Brushfield spots (spots in the iris)

Limbs - single palmar crease, wide gap between first and second toes (sandal gap)

Cardiac - Atrial and Ventricular septal defects

Other - short statue, duodenal atresia (narrowing)

95% of all Down Syndrome cases are caused by non-disjunction during meiosis I (75%) and meiosis II (25%).
NON-DISJUNCTION = FAILURE TO SEPARATE

4% of all Down cases are caused by TRANSLOCATIONS.

MOSAICISM has an effect on Down Syndrome - 1% of cases

Question 14

define Dosage Compensation

Answer 14

If we lose a chromosome, the fully expressed gene products from that chromosome are lost so we’ve lost 50% of our gene product (protein).

That might not be important because we may only need 10% of that gene product. If we need 100% of that chromosome then the loss of that chromosome will be devastating. That is why loss of an autosomal chromosome is almost always lethal.

Gain of one chromosome gives an increase of 33% of all fully expressed gene products (gone from 100% to 150% - 2 to 3)

GAIN OF CHROMOSOMES IS BETTER TOLERATED

NOTE: In women we only need one X so the other X is always switched off - X inactivation

Question 15

How can you be chromosomally one gender and phenotypically the other gender?

Answer 15

This is because of translocation.

The Y chromosome has a SEX DETERMINING REGION ON THE Y (SRY) - this is what makes males male.

If there is a translocation of the SRY from the Y to the X you can get an X chromosome with a male determining factor and a Y which has LOST the male determining factor so phenotypically the XX will be male and the XY will be female.

Question 16

What are genomic disorders

Give two examples of the two types

Answer 16

Caused by the loss or gain of DNA

Deletion Syndrome - e.g. Di George Syndrome

Duplication Syndrome - e.g. Charcot-Marie-Tooth disease type 1A

These may not be visible in the karyotype because they are micro-deletion syndromes.

Question 17

3 Symptoms of Di George Syndrome

What chromosome is affected

Answer 17

Cardiac abnormalities (e.g. tetralogy of Fallot)

Hypoplastic Thymus

Hypocalcaemia

Micro-deletion of 22q11.2 region containing the gene TBX1

Question 18

5 symptoms of Charcot-Marie-Tooth disease type 1A

What chromosome is affected

Answer 18

Muscle weakness

Hypotonia

Missing reflexes

Foot deformities - high arches or flat feet

Lack of sensation in hands and arms

Micro-duplication of PMP22 gene on Chr 17

Question 19

Describe dysmorphism

Answer 19

An unusual or abnormal physical feature

Question 20

What is chromosome banding and how is it written out

Answer 20

There is a standard human banding pattern due to the staining which is the same for everyone. The centromere is the start point. You number out from the centromere starting from 11.

It can be written in short hand in the following sequence:
Chromosome number
P or Q arm
Band number

Question 21

What is Monosomy X known as
What is the prevelance
6 symptoms
Treatment

Answer 21

Monosomy X - Turner Syndrome

1 in 3000 live female births

Symptoms
Generalised oedema and swelling in neck region can be detected in 2nd trimester.  
Low posterior hairline,
 short 4th metacarpals, 
webbed neck, 
aorta defect in 15% of cases 

In adults: short statue (without GH treatment), 
ovarian failure (infertility)  

Treatment - oestrogen replacement for secondary sexual characteristics and prevention of osteoporosis.
80% due to loss of X or Y chromosome in paternal meiosis.

Question 22

What is it known as when someone has an XXY genotype
What is the prevelance
5 symptoms

Answer 22

Kleinfelter’s Syndrome (47, XXY)

1 in 1000 male live births

Clumsiness, verbal learning disability
Taller than average, long lower limbs
30% - moderately severe gynaecomastia (enlargement of man’s breasts)
All infertile
Increased risk of leg ulcers, osteoporosis and breast carcinoma in adult life