Genetics Flashcards
How common are genetic diseases?
4-5% of all live births
30% of admissions to paediatric wards - congenital abnormalities
10% adults have disease with genetic component
5% common cancers such as breast and colon cancer due to underlying genetic predisposition
What is the role of a clinical geneticist?
Involved in making diagnoses
Explain diagnosis to family
Discuss prognosis
Discuss options available - genetic testing, screening, prenatal diagnosis
Refer to appropriate specialist for management
Help people understand and adapt to medical, psychological, and familial implications of how genetic contributes to disease
Guide individuals/families in discussions about test result interpretation, prevention, medial management, and options for prenatal diagnosis
Not involved in diagnosis
What referrals do clinical geneticists get?
Preconceptual - genetic testing Antenatal - scans/tests Paediatrics - not meeting milestones ect Carrier testing Adult onset conditions Post mortem
What are the categories of genetic disorders?
Single gene disorders - mendelian inheritance
Chromosomal disorder - affects thousands of genes so multiple organ systems affected
Multifactorial - several genes acting with environmental influences, usually only affects one organ system
Spectrum of conditions
Name 3 types of genetic disease
Down’s syndrome
CF
Huntington’s disease
Haemophilia
Name 3 types of multifactorial disease
Spina bifida
Cleft lip/palate
Diabetes
Schizophrenia
Name 3 types of environmental disease
Poor diet
Infection
Accidents
Drugs
What are the different types of single gene disorders?
Autosomal dominant
Autosomal recessive
X-linked
What can cause chromosomal abnormalities?
Changes in number/structure
Entire chromosomes/individual chromosomes/alterations within individual chromosomes
What is polyploidy?
Increase in number
What is it called where you lose a chromosome?
Monsomy
What is it called where you gain a chromosome?
Trisomy
What is euploidy?
Normal number of chromosomes
What is aneuploidy?
Abnormal number of chromosomes
What is a common cause of aneuploidy?
Non-disjunction
Failure of chromosomes to separate at anaphase
Can occur in meiosis 1/2
Name 2 causes of chromosomal conditions
Unbalanced translocation
Non-disjunction
What should you do if a baby has chromosome translocation?
Test the parents
How common in aneuploidy?
35-70% of early embryonic deaths and spontaneous abortions caused by aneuploidy
1 in 170 live births
What are the possible clinical effects of cytogenetic abnormalities?
Congenital abnormalities
Delayed development - usually severe
Dysmorphic features
Small stature, microcephaly, failure to thrive
In adults - infertility, stillbirths, miscarriages
How might autosomal dominant inheritance present in a family?
Each child has 50% chance of inheriting mutation
Equally transmitted by men and women
Often affected individuals in multiple generations
Vertical transmission
Mutation transmitted from male to male
Sex can be limited
Only one copy of gene pair altered
May have variable penetrance and often variable expression
Possibility of new mutations
Gonadal mosaicism may occur
Name 3 causes of autosomal dominant inherited conditions
Adult PKD Familial hypercholesterolaemia Marfan's Huntington's disease Familial breast and ovarian cancer
What is gonadal mosaicism?
Condition in which the precursor cells to ova and spermatozoa are a mixture of 2 or more genetically different cell lines
What is autosomal recessive inheritance?
2 germline mutations to develop disease
How might autosomal recessive conditions present in families?
Equally transmitted by men and women
Unless consanguinity usually only one generation affected
Both parents heterozygous carriers
1 in 4 recurrence risk for siblings
2 in 3 carrier risk for unaffected siblings
Usually low risk for children of affected person or half-siblings - depends on population carrier frequency
Increased risk in consanguineous families
Name 3 conditions that are autosomal recessively inherited
CF PKU Haemochromatosis SMA Non-syndromic sensori-neural deafness
How might x-linked inheritance present in families?
Genes carried on x chromosome
More males than females affected
Females carriers - 50% sons affected, 50% daughters carriers
All daughters of affected male are carriers
None of offspring of affected male have disorder
Possibility of new mutations
Gonadal mosaicism may occur
Influenced by x inactivation
Name 2 causes of x-linked diseases
Duchenne and Becker muscular dystrophy
Fragile X
Retinitis pigmentosa
Ocular albinism
Name 3 types of non-mendelian inheritance
Multifactorial
Imprinting
Mitochondrial inheritance
Mosaicism
What causes neural tube defects?
Multifactorial
What can decrease the chance of neural tube defects?
Taking folic acid in pregnancy can decrease risk by up to 70%
What is the risk of neural tube defects if have an individual in family already affected?
1 sibling 2%
2 siblings 10%
Parent 4%
What can increase risk of neural tube defects?
Maternal diabetes
What causes mitochondrial disorders?
Exclusively maternally inherited deriving from those present in cytoplasm of ovum
Tends to affect those tissues that use the most energy
What is in the mitochondria?
Contain own circular 16.5Kb chromosome
What is heteroplasmy?
Mixed population of normal and abnormal mitochondria
Name 3 types of mitochondrial disease
MELAS - mitochondrial encephalopathy lactic acidosis stroke like episodes
MERRF - myoclonic epilepsy, ragged red fibres
DIDMOAD - mitochondrially inherited DM and deafness
Leber’s hereditary optic atrophy
What is genomic imprinting?
For most genes both copies are expressed
Some genes are maternally or paternally expressed - imprinting
Name 2 conditions that involve genomic imprinting
Prader-Willi
Angelman’s
Caused by cytogenetic deletions of the same region of chromosome 15q or by uniparental disomy of chromosome 15 (both copes of 15 come from same parent)
How does Prader-Willi syndrome present?
Neonatal hypotonia and poor feeding
Moderate mental retardation
Hyperphagia and obesity
Small genitalia
What caused Prader-Willi syndrome?
Caused by deletion in paternally inherited chromosome 15 or maternal uniparental disomy
How does Angelman’s syndrome present?
Happy puppet unprovoked laughing/clapping Microcephaly Seizures Ataxia Broad based gait
What causes Angelman’s syndrome?
Deletion in maternally inherited chromosome 15 or parental uniparental disomy
How often are cancers referred to clinical geneticits?
Around 50% of all referrals
What genes can cause breast and ovarian cancer?
BRCA1 and 2
What genes can cause bowel cancer?
Lynch
(A)FAP
MYH
Other polyposis genes
What is fragile x syndrome and how is it inherited?
Most common form of learning disability
X-linked
How common is fragile x syndrome?
Females don’t always have clinical features - approx 30% have some learning disability
1 in 2000 males affected (approx 80% undiagnosed)
1 in 600 carriers (some of premutation)
How does fragile x syndrome present?
IQ of young boys seems to steadily decline so as children may only be mild/moderately affected, adults males usually have an IQ under 50
Long narrow face
Prominent ears
Hyper-extensible joints
Emotional and behavioural problems common in both sexes if affected
How does the genetics of unaffected individuals differ from those with fragile x syndrome?
Unaffected - 10-50 copies of triplet repeat CGG
Fragile X - 50-200 premutation unstable during cell division likely to expand to full mutation of more than 200 repeats
When is the heel prick test done in children?
Day 5 of life
What is tested for in the heel prick test?
Sickle cell disease CF Inherited metabolic disorders - Phenylketonuria - Medium-chain acyl-CoA dehydrogenase deficiency - Maple syrup urine disease - Isovaleric acidaemia - Glutaric aciduria type 1 - Homocystinuria
