Genetics 1- Mrs. Jones' First Consultation Flashcards
What is the prevelance and mortality of Congenital Abnormalities
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.
What are the 8 types of Classification of Congenital Abnormalities or Birth Defects
Malformation
Disruption
Deformation
Sequence
Syndrome
Dysplasia
Association
Dysmorphism
Describe malformation
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.
Describe Disruption
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.
Describe Deformation.
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.
Describe Syndrome
Consistent pattern of abnormalities with a specific underlying cause e.g. Down Syndrome
This includes chromosomal abnormalities
Describe Dysplasia
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
Describe Sequence
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.
Describe Association
Non-random occurrence of abnormalities NOT explained by syndrome.
Cause is typically unknown.
E.g. VACTERL association - Vertebral, Anal, Cardiac, Tracheo-Oesophagal, Renal, Limb
What are the three types of chromosome abnormalities
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
What is Autosomal Aneuploidy
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
What are Partial Aneuploidy (TRANSLOCATIONS)
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.
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
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
define Dosage Compensation
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
How can you be chromosomally one gender and phenotypically the other gender?
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.
What are genomic disorders
Give two examples of the two types
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.
3 Symptoms of Di George Syndrome
What chromosome is affected
Cardiac abnormalities (e.g. tetralogy of Fallot)
Hypoplastic Thymus
Hypocalcaemia
Micro-deletion of 22q11.2 region containing the gene TBX1
5 symptoms of Charcot-Marie-Tooth disease type 1A
What chromosome is affected
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
Describe dysmorphism
An unusual or abnormal physical feature
What is chromosome banding and how is it written out
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
What is Monosomy X known as
What is the prevelance
6 symptoms
Treatment
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.
What is it known as when someone has an XXY genotype
What is the prevelance
5 symptoms
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
