Genetics Flashcards
autosomal dominant inheritance
· More than one generation involved
· Male to male transmission
· Males and females affected with equal severity
· Penetrance: affected person showing clinical symptoms
· Expressivity: variation in clinical presentation
autosomal recessive inheritance
One or more affected children with unaffected parents
Usually only one generation involved
Males and females affected with equal frequency and severity
A higher incidence of consanguinity
X-linked inheritance
Usually only males affected
More than one generation involved with the disease appearing to be passed on through normal females
No male to male transmission
X inactivation
Carrier females affected by X-linked disorders as a consequence of X-inactivation/lyonization -> random, normal X chromosome switched off in excess of cells leaving diseased X= manifestation of disease
Fragile X Syndrome
commonest non chromosome cause of mental retardation
- 1:4000
Symptoms:
- Mild-severe mental retardation
- Macroorchidism (post pubertal)- abnormally large testes
- Long face, prominent jaw, thick nasal bridge, large ears
- Joint hypermobility
- Autistic features
Consanguity of first, second and third degree relatives
first= 50% (100% if identical) second= 25% third= 12.5%
Fetal Sex on Maternal Blood- cell free fetal DNA (cffDNA)
- Originates from placental trophoblast & shed into maternal blood stream, detectable from 4-5w gestation (increases with progression)- Can be analysed to detect Y specific sequence of male
- 3-6% of total DNA in maternal plasma, cleared rapidly post delivery
- Used for early non-invasive prenatal determination of sex for foetuses at risk of X linked disorders (avoid invasive CVS for female foetus)
Chorionic Villus Sampling- invasive
- Piece of placenta -> DNA extraction and chromosome analysis
- performed 11w gestation, miscarriage risk= 1.5-2%
- PCR based test (DNA extracted without culture), result in three days
Amniocentesis
- Removal of 10-20ml amniotic fluid under ultrasound control, contain cells from baby and placental membranes: chromosome analysis and DNA molecular analysis
- Performed 15w gestation onwards, miscarriage risk= 0.5-1%
Amnio-PCR
- Amplification of polymorphic markers on chromosomes 21, 18 and 13 based on limited PCR cycles= quantification of results
Preimplantation Genetic Diagnosis
IVF creation of embryo from egg and sperm of couple, each embryo tested for particular genetic disorder and one unaffected embryo is transferred into womb -> pregnancy
- for couples at risk of having a child with a single deep gene disorder or chromosomal disorder
Criteria for PGD (NHS funded)
known genetic condition, female age >39, no unaffected living child, female BMI< 30, non-smoker, AMH>/= 6, antral follicle count >8
Haemoglobinopathies Antenatal Screening Programme
- Screening for sickle cell anaemia and other haemoglobin variants based on Family Origin Questionnaire to assess risk, women and/or partners in high risk groups
- Screening for thalassemia based on inspection of routine blood indices
Screening for Trisomy 21, Trisomy 18 & Neural Tube Defects
- First trimester screening (nuchal transparency, HCG, PAPP-A) offered 11-14w
- Second trimester screening (missed first) offered 15-20w, measure AFP, HCG, unconjugated oestridiol & inhibin A
High HCG: AFP ratio increases
chances for Down Syndrome
AFP<2 multiples of median adjusted for maternal wight indicates
increased risk of neural tube defect, 90% identified in second trimester detailed screening
When is ultrasound screening for fetal anomaly carried out in low risk women?
Ultrasound screening for fetal anomaly in low risk women performed 18-20w gestation
endophenotypes
if 1 person in family has disease, other people in family may have it with low expressivity eg. on the spectrum
How do you know if a disease is genetically determined?
- Segregation analysis– this looks for patterns in the family history of affected individuals
- Using twin studies which compare the concordance of disease between monozygous (identical) twins to the concordance of the same disease in dizygous (fraternal) twins
Both of these techniques provide a quantitative measure of how “genetic” a disease is. Diagnostic genetic testing is currently only available in mendelian disease.
Newborn Screening in Scotland
- phenylketonuria (PKU)
- congenital hypothyroidism (CHT)
- cystic fibrosis (CF)
- medium chain acyl-CoA dehydrogenase deficiency (MCADD)
- sickle cell disorder (SCD)
- hearing loss
Phenylketonuria (PKU)
- 1/6000 in Scotland
- clinically silent in first months
- eczema, hypopigmentation, severe developmental delay by toddler age, ‘mousy’ smell to urine (from build-up of intermediate phenyl-acetate)
- all babies have testing at 7 days
what mutation leads to PKU?
mutation in both copies of PAH gene- no phenylalanine hydroxylase activity > build-up of phenylalanine (neurotoxin) leading to intellectual disability
Treatment for PKU
phenylalanine-restricted diet started <21 days, continue diet for life and leads to normal outcome in most children
Criteria for population based screening:
- Well defined disorder
- Known incidence
- Significant morbidity or mortality
- Effective treatment available
- Period before onset during which intervention improves outcome
- Ethical, safe, simple and robust screening test
- Cost effective
Criteria for Presymptomatic Genetic Testing- medical reasons
- If done for medical reasons:
o Should result in a preventative intervention
o Family implications need to be considered - Testing of children is appropriate if intervention starts in childhood
when is Pre-symptomatic Genetic Testing carried out for non-medical Reasons?
Carried out in adult onset neurodegenerative disorders eg. HD:
- autosomal dominant
- DNA diagnosis available
- No effective treatment
- No accurate prediction of age of onset
- Restricted to adults
what kind of mutation is the majority of developmental disorders caused by?
de novo mutation (78%)
Cornelia de Lange- causes, symptoms
- caused by mutation of NIPBL (loading protein during metaphase for cohesion)
- causes severe limb malformation, characteristic facial features, short stature
- mutations in SMC1A, RAD21, SMC3 give similar phenotypes
Modularity
mutations in different components in the same complex causing similar disorder
There are specific genes commonly seen associated with severe mental retardation > chromatin associated protein has a general effect on genes expressed
- effects can be so severe because transcription of many different genes if affected by a single protein
channel proteins are common targets for
genetic epilepsy & epileptic encephalopathies
What is the difference between somatic and germline mutations?
Somatic mutations- non germline tissues, non-heritable
Germline mutations- present in egg/sperm, heritable, cause cancer family syndrome
Difference between familial and sporadic retinoblastoma?
- Familial= presents in childhood & bilateral, multifocal
- Sporadic= presents later on & unilateral, unifocal
Knudson’s 2 Hit Hypothesis
If first hit is a germline mutation, second somatic mutation more likely to enable cancer
Mutations and Inheritance of Tumour Suppressor Genes
Tumour suppressor genes control cell growth and differentiation and function as ‘cellular recessives”- both alleles must be affected but a first hit germline mutation is inherited in a dominant fashion.
-% of RB is familial
risk of - is increased in germline mutation
10%
non-ocular tumours
Neurofibromas Type 1 (NF1)
· Autosomal dominant · Affects 1 in 2,500 · Multisystem disorder · Dominant · Fully penetrant · Highly variable expressivity- Great variability between affected individuals in the same family
NF1 gene function
The NF1 gene (v large) on chromosome 17 encodes the protein neurofibromin. Neurofibromin suppresses Ras, a potent activator of cell growth and proliferation.
Clinical Features of NF1
· Neurofibromas (anywhere in body)- cutaneous, subcutaneous, nodular, plexiform
· Other skin manifestations- axillary freckling
· Lisch Nodules- in the eye
· Optic Glioma- growth around optic nerve, usually asymptomatic and can present with deteriorating vision, 15%
- Scoliosis- 10%, usually v mild, small number with severe presentation
- Learning disability- usually mild, 30-50%
- Large head
NF1 Cancer Predisposition
- Malignant tumor of the peripheral nerve sheath
o Life time risk of 13%
o Usually from pre-existing plexiform neurofibroma - Astrocytoma 2%
- Phaeochromocytoma 0.7%
- Rhabdomyosarcoma 1.4%
Von Hippel Lindau Disease
- Autosomal dominant
- Affects 1 in 35,000 individuals
- High penetrance
- Associated with a wide variety of tumours
vHL protein function
The vHL protein suppresses tumour growth and downregulates angiogenic factors.
vHL mutation identification
~90% of individuals with a clear diagnosis of vHL will have mutation identified- myoclonic testing is 1st line investigation
Screening Regimen for vHL (yearly)
MRI of brain and spine (2-3 yearly)
Ages 5-18
- Eye/retinal examination
- 24 hour urine collection for catecholamines
Ages 18-65
- Eye/retinal examination
- Physical examination
- 24 hour urine collection for catecholamines
- MRI of abdomen
If tumour found early- easier to treat with less severe complications
Familial Adenomatous Polyposis
- Autosomal dominant
- 1 in 10,000
- polyps develop during second decade
- colonic malignancies third decade
- Associated features
o CHRPE
o Desmoid tumours
o Osteomas
APC mutation types
APC (large) mutations are mostly truncating mutations. You can also have attenuated FAP- milder, later onset and better prognosis.
what is genomic imprinting?
Genomic imprinting is the difference in gene expression depending on whether a gen is maternally or paternally inherited.
what does genomic imprinting lead to?
Leads to functional hemizygosity i.e loss of biparental contribution
Examples of genetic imprinting
Example: deletion of 15q11.13 region on maternal chromosome= Angelman’s but on paternal= Prader Willi
Angelman’s Syndrome
- Severe global developmental delay
- No speech
- Inappropriate laughter
- Drooling
- Seizures
- Cannot walk without help
- No family history
Prader Willi Syndrome
- Floppy at birth, poor feeding
- Short stature, small hands and feet
- Hyperphagia and obesity
- Hyponadism
- Mental retardation (mild to moderate)
