Genetics Flashcards
Aneuploidy of Downs Syndrome
Trisomy 21
Clinical features/symptoms of Downs Syndrome
Cardiac problems: significant leading to major cardiac surgery
-Septal defects
-Atrioventricular canal
Limb problems:
-Single palmar crease
-Sandal gap (wide gap between the first and second toes)
Craniofacial problems:
-macroglossia (abnormally large tongue)
-small ears
-epicanthic folds (vertical fold of skin from the upper eyelid that covers the inner corner of the eye)
-brushfield spots (tiny white spots around the iris of the eye)
Newborn problems:
-hypotonia (decreased muscle tone=floppy baby syndrome)
-lethargy
-excess nuchal skin
Other problems:
-short stature
-duodenal atresia
-low IQ but advanced social skills
Three different chromosome aberrations leading to Downs Syndrome
1) Trisomy 21 (in 95% of cases)
2) Translocation (Robertsonian specifically and in 4% of cases)
3) Mosaicism (1% of cases)=abnormal cell population in the body
Define monosomy
Loss of a single chromosome and almost always lethal leading to miscarriage
Define disomy
Normal pair of chromosomes
Define trisomy
Gain of a single chromosome and can be tolerated for specific chromosomes
Define tetrasomy
Gain of 2 chromosomes (although extremely rare) and can be tolerated for specific chromosomes
Aneuploidy of Patau’s Syndrome
Trisomy 13
Aneuploidy of Edward’s Syndrome
Trisomy 18
Clinical features of Patau’s Syndrome
Cardiac problems: -Septal defects -Patent ductal arteriosus Holopresencephaly (structural malformation of the brain which often affects facial features giving a cleft lip and orbital hypotelorism) mental retardation
Clinical features of Edward’s Syndrome
Cardiac problems: -Septal defects -Patent ductus arteriosus Kidney malformations: -Horseshoe kidney Digestive tract defects: -Omphalocele (where the infants intestine or other abdominal organs are outside of the body because of a hole in the belly button area) -Oesophageal atresia (upper part of the oesophagus does not connect with the lower part of the oesophagus and the stomach) Mental retardation
Prenatal features of Turner’s Syndrome
-generalised oedema and neck swelling which occurs in the second trimester (13 weeks to 28 weeks)
Clinical features of Turner’s Syndrome in newborns/children
-Low posterior hairline
-low set ears
-broad chest
-oedematous hands/feet (both in utero and postnatally)
-webbed neck (characteristic)
-normal intelligence (brain development not impaired)
Aortic defects:
-coarctation (congenital narrowing of a short section of the aorta)
-valve defects
Urinary defects:
-horseshoe kidney
Complications in adults from previous Turner’s Syndrome symptoms
-Short stature (averaging 145cm)
Ovarian failure leading to primary amenorrhoea (failure to establish menstruation by 16 years of age)
-Infertility
Diabetes
-Hypothyroidism (underactive thyroid gland)
Treatments of Turner’s Syndrome
-Incurable but treatments minimise symptoms (growth hormones, oestrogen replacement and multidisciplinary management/follow up)
Causes of Turner’s Syndrome
- 80% of cases due to loss of X chromosome or Y chromosome in paternal meiosis)
- 20% of cases due to other causes like single arm deletion, ring chromosome or mosaicism)
Clinical features of Klinefelter’s Syndrome
- mild learning disability
- taller than average (long lower limbs)
- infertility
- gynaecomastia (male breast tissue swells and becomes larger than normal)
Klinefelter Syndrome patients are at risk of?
- leg ulcers
- osteoporosis
- breast carcinoma
Define congenital defect/abnormality/birth defect
Condition present from birth
Clinical features of Di George Syndrome
C=cardiac anomalies (interrupted aortic arch and the tetralogy of fallot)
-The tetralogy of fallot includes overriding aorta, pulmonary stenosis, right ventricular hypertrophy and ventricular septal defect
A=abnormal facies (low set ears, widely spaced eyes)
T=thymic hypoplasia
C=cleft palate
H=hypocalcaemia
2
2
-learning difficulties and difficulty feeding
Clinical features and prognosis of Charcot-Marie-Tooth disease type 1A
- foot drop
- distal muscle wasting
- pes cavus (claw foot)
- absent reflexes
- lack of sensation in upper/lower limbs
- slow nerve conduction velocity
- incurable but treatment minimises symptoms with physiotherapy and corrective surgery
Define malformation
A morphological defect of an organ, part of an organ or a larger region of the body resulting from an intrinsically abnormal development process (primary structural defect of an organ/tissue)
- single organ shows a multifactorial inheritance (many factors are involved in causing the birth defect, both genetic and environmental)
- Abnormal developmental pathway from beginning
Define disruption
- A morphological defect of an organ, part of an organ or a larger region of the body resulting in the extrinsic breakdown of, or interference with, an originally normal development process (secondary structural defect of an organ/tissue)
- Normal development pathway is disrupted by an extrinsic factor giving an abnormal result
- Irreversible
- not caused by genetic factors but they can predispose
Define deformation
- Abnormal form, shape or position of part of the body due to mechanical force (abnormal mechanical force distorts/disrupts the structure)
- Potentially reversible
- Change in development from normal to abnormal by mechanical force
- Occurs late in pregnancy and has good prognosis as underlying structure is normal
Define dysplasia (congenital defect)
- Abnormal organisation (disorganised layout) of cells into tissues and its morphological results
- genetical cause
Define syndrome
- Consistent pattern of abnormalities with a specific underlying cause
- abnormalities are though to be pathogenetically related and not representing a sequence
Define association
- Non random occurrence in two or more individuals of abnormalities not explained by syndrome and hence have an unknown cause (causality is not identified)
- Also not known to be a polytopic defect (defects in one concentrated area of the body), sequence or syndrome
Define sequence
- Pattern of multiple abnormalities initiated from a primary factor
- primary factor is a single known or presumed prior anomaly or mechanical factor
- one event leads onto another
- the primary factor can be genetic
Give an example of malformation
-Aortic septal defect (abnormal hole in the septum between the two upper chambers of the heart)
-The aortic septal defect occurs at an early stage, will not be fixed by itself and will continue to grow/develop over time
Another example is cleft lip
Give an example of disruption
- Amniotic band syndrome
- The fibrous amniotic bands developed from the inner lining of the amniotic sac act as a tourniquet and wrap around the digits, restricting the blood flow and causing digital amputation or impediment of normal development
Give an example of deformation
- Hip dislocation
- Club foot (=talipes equinovarus,one or both feet point down and inwards)
- Club foot can be reversed/straightened out through physiotherapy and in some cases, corrective surgery
Give an example of dysplasia
-Thanatophoric dysplasia (severe skeletal disorder)
-Thanatophoric dysplasia is characterised by a mutation in the single FGFR3 gene
-It is considered to be autosomal dominant
-infants with the disorder are often stillborn or die shortly after birth from respiratory failure
Clinical features include:
-Short limbs
-Large skull leading to an enlarged head
-Narrow thorax resulting in underdeveloped lungs
-folds of redundant skin on the arms and legs
-wide spaced eyes
-bowed long bones (in type 1)
Give an example of syndrome
-Downs Syndrome due to a single extra copy of chromosome 21
Give an example of association
-VACTERL association of birth defects affecting many body systems
Give an example of sequence
- Potter sequence
- Primary factor is an abnormality in the urogenital tract (bilateral renal agenesis or urethral atresia)
- Leads to reduced urine output and then oligohydramnios (decrease in the amount/low volume of amniotic fluid in the amniotic sac)
- Secondary abnormalities then result=clubbed feet, pulmonary hypoplasia and potter facies (all have a common primary factor although effect is on different parts of the body)
Cause of Di George Syndrome
Micro-deletion in chromosome 22 (loss of 30-50 genes including TBX1)
Cause of Charcot-Marie-Tooth disease Type 1A
Micro-duplication in chromosome 17 (observe duplication of PMP22 during this)
Effects of advanced maternal age on Down’s Syndrome risk
- Strong association of increased syndrome risk with an increase in maternal age
- Significant risk increase from mid 30’s onwards
Incidence of Downs Syndrome at birth
Approx 1:700
Survival time for Patau Syndrome
Patients rarely survive past 1 month
Survival time for Edward’s Syndrome
Less severe compared to Patau’s, but the majority of patients still die within the first year of life
TBX1
Gene coding for a transcription factor involved in the regulation of many developmental processes
PMP22
Gene coding for an integral membrane protein which is a major component of myelin in the peripheral nervous system
Define aneuploidy
The loss or gain of one or more chromosomes
Monosomy X
- Only viable monosomy
- Observed in Turner’s Syndrome
Genotype of Klinefelter’s Syndrome
47, XXY
Genotypes of the rare Klinefelter Syndrome variants
48, XXXY
49, XXXXY
Characteristics of autosomal dominant
- At least one affected parent
- Transmitted from either parent (male or female)
- Male and female offspring both affected
- Vertical transmission as there is an affected family member in every generation
Example of an autosomal dominant disease
Huntington’s Disease
Define genetic anticipation
/
Characteristics of autosomal recessive
/
Example of an autosomal recessive disease
Cystic fibrosis
Characteristics of X-linked recessive
/
Example of an X-linked recessive disease
Haemophilia
MELAS
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
Symptoms of MELAS
/
LHONS
Leber’s Hereditary Optic Neuropathy
PKU
Phenylketonuria
Clinical features of PKU
- blond hair
- blue eyes
- musty odour from excess phenylacetate
- light skin (lack of melanin)
- eczema
MCADD
Medium-chain Acyl-CoA dehydrogenase deficiency
List the single congenital abnormalities
Malformation, disruption, deformation and dysplasia
List the multiple congenital abnormalities
Syndrome, association and sequence
Possible extrinsic factors causing disruption
Infection, mechanical trauma, ischaemia (common=inadequate blood supply to the tissues)
Pulmonary hypoplasia in relation to Potters sequence
Incomplete development of the lung tissue
Potter facies
- flattened nose
- low set abnormal ears
- micrognathia (one or both jaws are unusually small)
- epicanthal folds (vertical skin folds from the upper eyelid covering the inner corners of the eye)
Disruption of a gene
When the breakpoint for translocation occurs in the middle of a gene, hence causing the functional deletion of that gene
Ratio for newborns with significant congenital abnormalities
1:50
Contribution of genetic factors to congenital abnormalities
- Approximately 40%
- Vast majority of contribution to abnormalities are from other multiple factors
Main difference between the multiple congenital abnormalities
Mechanism by which the clinical features/ symptoms are linked
Proportion of deaths occurring during the perinatal period and in childhood up to 10 years of age
- 20%-25% of all deaths
- congenital abnormalities are a large factor in terms of morbidity and mortality in the paediatric population
Clinical features of Potter facies
- abnormal ear lobation and low set
- micrognathia (undersized jaw)
- flattened nose
- epicanthal folds
Chromosomal set inherited from one parent
- 22 autosomes and 1 sex chromosomes (X or Y depending on yours and parents gender)
- haploid number were every chromosome is different (23)
Point mutations
Missense and nonsense
-change in one DNA base pair resulting in the substitution of one amino acid in the polypeptide chain
Missense mutation
- single nucleotide is replaced at one point giving a single incorrect amino acid
- may give a malfunctioning protein (not all the time)
Silent mutation
/
Nonsense mutation
/
Frameshift mutations
Insertion and deletion
Pedigree diagram features
- square=male
- circle=female
- dot inside shape=carrier for recessive condition
- sloping line from bottom left corner=person has died
- filled in shape=affected by genetic disease
- obtain details such as miscarriages, stillbirths, deaths etc for each partnership
- miscarriages represented as smaller shape, filled in with number of miscarriages labelled underneath
- ask if individual has children with other partners
- proband=person who is the starting point of the family’s genetic study=first person to be treated for a genetic disorder in family
- label with name (maiden name) and date of birth
