Genetics Flashcards
DNA structure
Deoxyxribrosenucleic acid. Double strand helix. Phosphate back bone chains lie in antiparallel. With complementary nucleic acids held together by weak hydrogen bonds.
DNA replication
Strands are separated by DNA helices, replication fork is formed with DNA polymerase. Leading strand formed continuously, with lagging strand made up of short okazaki fragments joined by DNA ligase
satellite DNA
repetitive DNA sequences very large series of simple repeats transcriptively inactive and clustered around centres of centromeres
Mitochondrial inheritance
derived from oocyte - maternal
Introns vs exons
Introns are non coding and spliced out
Transcription
DNA to RNA. Uracil instead of thymine. DNA unzipped by RNA polymerase allowing complementary RNA nucleotides to bond to the DNA forming antisense RNA strand
Complementary base pairs
A to T, C to G
Post-transcription modification
Poly A tail
non coding introns spliced out
5’ adenyl cap
Translation
Production of proteins from mRNA strand. mRNA travels to the ribosome. Promoter regions tell 30s and 50s subunits of the ribosomes to bind. tRNA molecules have an amino acid preloaded and bind to their complementary triplet codon. Peptyltransferase forms the polypeptide chain until stop codon reached
DNA code
Non overlapping, degenerate
Polymorphisms
variation in genetic code with no effect on phenotype
Somatic vs germline mutations
Somatic - sporadic adult onset no passage to offspring
Germline - passes to offspring. Predisposed to cancer 2 hit hypothesis
Substitution mutation
replacement of a single nucleotide.
Deletion and insertion
If not in multiples of 3 will lead to frame shift. Frame shift leads to complete change of amino acid sequence, can lead to early or late stop codons
Autosomal dominant
Manifests in heterozygotes. Only one mutant allele needs for expression. 50% passage to offspring. Seen in pedigree by male to male passage and about 50% of relatives affected
Pleuritropy
single gene leads to two or more unrelated effects in different body systems
Variable expression
different manifestations of disease in individuals with the same genetic condition
Penetrance
proportion of individuals with a genetic mutation who exhibit signs and symptoms of the disorder
Autosomal recessive
only manifest in homozygous individuals i.e. 2 copies of the defective allelle
EBV and cancer
Burkitts, craniopharyngioma, Hodgkin lymphoma
Proto-oncogenes
Promote cellular proliferation active during embryonic life and during tissue repair. Usually inactive
Oncogene
Mutated proto-oncogene capable of production uncontrolled cell division
RET (inactive)
Helps neural crest cells form the myenteric plexus in the gut. If inactive oncogene leads to absence of the parasympathetic ganglion cells in the gut = Hirschprungs
Hirschprungs PC
Often failure to pass meconium at birth, abdominal distention. Narrowing of sigmoid colon. May present later in life with FTT, chronic constipation and abdo distention.
Biopsy of myenteric plexus showing absence of ganglion cells. Mx = surgery
RET (active oncogene)
MEN 2 is due to a mutation in RET proto-oncogene, a tyrosine kinase receptor on cr 10. Leads to constant activation
MEN 2A
Medullary thyroid cancer, phaechromocytoma, parathyroid hyperplasia
MEN 2B
Marfanoid body habits, mucosal neuromas, medullary thyroid and phaechromocytoma
Tumor supressor genes
Designed to arrest cell growth, the brakes on the cell cycle
Rb
Tumour supressor gene which when mutated leads to retinoblastoma. Rare highly malignant childhood cancer developing from the retinal cells of the eye
- sporadic = unilateral
- heridatry = bilateral
PC = abnormal appearance of retina when viewed though pupil. Red reflex tested at birth, white reflex
Li Fraumeni
Mutation in p53. Guardian of the genome AD can give rise to leukaemia, osteosarcoma, early onset breast, brain and adrenal cancer
Colorectal Ca
Intestinal crypt cells are key to the initial event. 10% due to hereditary cause.
Mutator pathway
Mutator gene which allows other genes to gather mutations, this prevents recognition and repair. Increasing number of mutations confers malignancy
Lynch (HNPCC)
AD condition in DNA mismatch repair leading to huge numbers of polyps in proximal colon. 80% penetrance @ 40-60y/o
Cancer risk in lynch syndrome
colorectal, endometrial, ovarian, gastric and duodenal adenomas
Amsterdam criteria
3 colorectal tumors in family
2 succesive generations
1 < 50yo
Microsatellite instability
Defective DNA mismatch repair leads to susceptibility to mutation. Mismatch repair acts to correct errors made within DNA replication. Failure to work correctly leads to accumulation of errors. Slippage of daughter strand when replicating leads to DNA polymerase cleaving small fragments - microsatellites
High micro satellite instability
Indicative of Lynch.
BRAF V600E
Driver mutation in 15% of sporadic CRC, rarely seen in Lynch syndrome
Mx Lynch
75mg aspirin OD
2 yearly colonoscopy for survillance. uterine USS
+ve FHx = 1-2 yr upper GI endoscopy
family cascade testing
Mair Torre
Lynch syndrome + sebaceous skin tumors
Turcot
Lynch + glioblastoma
FAP + medulloblastoma
FAP
1000’s of colonic adenomas. 100% penetrance by 40yo
Usually clinically silent occasionally may present with wt loss, anaemia or PR bleeding
FAP and APC
Loss of tumour suppressor gene responsible for producing adenomatous polyposis coli. AD. Attenuated APC has better prognosis with few polyps
Extracolonic manifestations
Desmoid tumours, gastric polyposis, papillary thyroid caner, congenital hypertrophy of retinal pigment epithelium
Mx FAP
genetic screening of family members
close colonic surveillance
prophylactic colectomy if 30+ advanced polyps detected
Cowdens syndrome
AD condition in PTEN1 tumour stressor gene gives rise to multiple bengin hamartomas found on the skin, mucous membranes, in the thyroid gland and breast tissue
Increased risk of breast, follicular thyroid and endometrial cancer
Peutz-Jeghers
AD conditon with presence of benign harmatous polyps in the GI tract and hyper pigmentation of the oral mucosa
Increased risk of GI, pancreatic, breast, uterine, testicular
CRC aetiology
80% sporadic, 20% familial with unknown causes of this 5% is thought to be attributable to lynch/FAP
Population CRC screening
one off flexisigmoidoscopy @ 55y/o
feacal occult blood 2 yearly from 60-74
BRAF V600E +ve/ MSI
1 relative < 50 or 2 relatives 60 = 2yrly colonoscopy from 25 y/o
If -ve 5 yearly from 50y/o
Diagnosing AD disorders
Clinical diagnosis, specific gene test i.e. FBN1 - Marfans,
suspected cause ? = gene panel, whole exome sequencing. Diagnosis from pedigree where gene testing may have been normal - new mutation
De novo mutations
new mutations found in generations
Anticipation
Using triplet repeats disorder is passed onto the next generation where it manifests at a younger age and is often more severe
Genetic heterogenicity
Single phenotype may be caused by any one of a number of alleles
Triplet repeat disorders
All demonstrate anticipation. Mutation causes and increased number of randomly repeated trinucleotides
Huntingtons PC
AD disease which due to defects in the HTT gene leads to progressive brain cell death
PC chorea, restlessness, poor coordination, unsteady gait, difficulty speaking, insomnia, dementia, personality changes, reduced cognition
Anticipation in Huntingtons
CAG repeats dictates the severity of the disease
< 26 = normal
27-35 = premutation, alleles confer worse prognosis for next generation
36-39 = reduced penetrance but symptomatic
40+ = fully penetrant
Mx huntingtons
MDT, SALT, dietician, physio, tetrabenazine to reduce chorea
Myotonic dystrophy
AD DMPK gene progressive muscle wasting and weakness, cataracts, arrhythmias, infertility, frontal balding, myotonia
> 2000 repeats onset in early childhood or incompatible with life
Long QT syndrome
Predisposition to delay of depolarisation due to channelopathies leading to increased risk of tornadoes de points and VF. ECG shows QTc >440m/s
Displays genetic heterogeneity where many different gene mutations cause the same phenotype
Marfan’s syndrome
Connective tissue disorder with reduced extracellular microfibril formation and disrupted elastic fibres. Demonstrates variable expression with different family members presenting with different presentations despite the same genetic condition
Ghent criteria - major
Ectopic lentis
Dilation of aortic root/dissection of aorta
Lumbosacral ectasia - dural thickening may - back pain
Pectus cavinatum/excavatum
FBN1 mutation
Hypermobile joints - wrist and fingers
Other signs of marfans
Archnodactyl, high arched palate, tall and skinny, mitral valve prolapse, spontaneous pneumothorax, myopia, cataracts, pes planus
Genetics Marfans
AD approx 80% linked to FBN1 mutation - missense mutation resulting in extracellular matrix containing 35% less fibrin 1. 20% de novo mutation
Mx Marfans
B-blocker to reduce dilation of aortic root
Prophylactic surgery of mitral valve/aortic root
Yearly echo
NF1
1/3000 people skin pigmentation and growth of tumours on nerves skin and brain. AD 100% penetrance defect in NF1 gene which makes neurofibroma a tumour suppressor
Diagnosis of NF1
2 of the following criteria >6 cafe au last spots freckling @ inguinal region or axilla optic glioma Lisch nodules - brown translucent mounds on iris >2 neurofibromatoms
Complications of NF1
30% = nerve compression giving pain, weakness and parathesia
epilepsy
5% risk of optic glioma, astrocytoma and other malignant conditons
Tuberous sclerosis
Rare condition with 75% of mutations occurring de novo
PC - facial rash of angiofibroma
hypomelanotic patches
fungal fibromas - raised nodules @ finger nails
retinal nodular hamartomas
Can lead to seizures, ADHD, poor IQ, renal failure and cysts, cardiac rhabdomyomas
Non invasive prenatal diagnosis
Maternal blood sample sent to test for fetal DNA @ 8 weeks
Preimplantation genetic diagnosis - PGD
Genetic profiling of embryos prior to implantation
Spinal muscle atrophy
AR condition involving degeneration of anterior horn cells in spinal cord. Type I and II onset before 12 and are usually fatal before 6months. III and IV begin in adults and confer a better prognosis
PC SMA
Progressive UMN and LMN weakness, focal asymmetry, dysphagia and dysarthria, fasciculation
CF
Carrier incidence of 1/20 life expectancy of 42y/o. AR defect causing defective CFTR gene. This is responsible for a transmembrane chloride channel. Different mutations of the gene have effects from misfolding to complete dysfunction. A defective CFTR channels leads to increased Na+ movement from apical membrane to balance the intracellular charger. H20 follows the Na+ leading to sticky viscous mucus. Commonest is F508
PC CF
Lungs - cilia are unable to waft the viscous mucus leading to recurrent infections - bronchiectasis, fibrosis and cor pulmonale. Risk of rare infections - pseudomonas, aspergillum
GI tract - thick mucus blocks pancreatic secretions leading to malabsorption syndromes and steatorrhea. Enzymatic destruction of the pancreas = DM
- Can present in children as meconium ileus/FTT
Males approx 95% infertile due to congenital absence of vas deferens.
Chorionic villus sampling
Sampling of placental tissue and analysis with FISH/PCR. Earliest technique at 10-12 weeks
Risk of choriamnioitis, 1% of miscarriage, oligohydramnios
Aminocentesis
Sample of amniotic fluid from 14-16wks. Lower risk of miscarriage. SE - chorioamniotis, preterm labour
Fetal alcohol syndrome
PC microcephaly, smooth philtre, palpebral fissure, developmental delay, thin upper lip
Tetragenic drugs
ACEi, warfarin, valproate, lithium, phenytoin, methotrexate
Teratogenic infections
CMV - chorioretinitis, deafness
DM - 2-3x risk of congenital abnormalities, heart defects and neural tube
Rubella - 1st trimester PDA, pulmonary artery stenosis
Toxoplasmosis - hydrocephalus, microcephaly, cataracts
Other teratogenic agents
radiation, alcohol, maternal illness - SLE
Other teratogenic agents
radiation, alcohol, maternal illness - SLE
Downs syndrome
Trisomy 21. Increased risk with maternal age. If increased nuchal translucency on USS.
Triple test of - PAPP-A, bHCG and USS
PC Downs
hypotonia, sleepy, excessive nuchal skin @ newborn
facial - epicanthic folds, brushfield spots in eyes, protruding tongue, small ears, upward sloping palpebral fissures
limbs - singular palmar crease, wide 1st-2nd toe gap, small middle phalanx of 5th
Cardiac - congenital heart defects in 45%, VSD, PDA and tetralogy of ballot
Hirshcprungs and duodenal atresia
Complications of downs
low IQ, increased risk of alzheimers and ALL, epileptic seizures, poor fertility, thyroid problems
Genetics of Downs
94% full trisomy due to non disjuncture at meiosis
4% robertsonian translocation where hybrid chromosomes are formed of 2x long and 2x short arms
- this can be balance or unbalance (loss of genetic material)
2% mosacism. Non disjuncture @ mitosis. Often better prognosis higher IQ
CHARGE syndrome
Coloboma of eye Heart defects Atresia of choane - nasal passage narrowing Retardation of development GU abnormalities Ear abnormalities and hearing loss
Aneuploidy
Abnormal number of chromosomes
Structural rearrangement
Balanced - no loss or gain of genetic material required karyotyping to detect as clinically silent. Increased risk of passage to offspring
Unbalanced - loss of genetic material leading to phenotype detectable on microarray
Edwards PC
Trisomy 18. Only 5% survive to term - 3% live to 10y/o
PC - low birth wt, growth retardation, clenched fists overlapping fingers, small jaw and mouth, structural heart defects, oesophageal atresia, webbing of toes, cleft palate
Translocations
transfer of genetic material from one chromosome to another.
Reciprocal = breakage of cr and exchange, identified via FISH
Robertsonian = breakage of atrocentric chromosomes - 13,14,15,21,22 close to centromeres
Mosacism
2+ cell lines that differ in their genetic constitution but have the same genetic origin. Non disjuncture at mitosis
Patau’s
Trisomy 13 80% live only 1 year.
PC - scalp defects, dextrocardia, low set ears, rocker bottom feet, micropthalmia, exomphalos, post axial polydactyl
Turners Syndrome
45X - The only viable monosomy seen in 1/5000 female births
PC Turners
PC short stature, webbed neck, widely spaced nipples, puffy feet and extremities at birth, small ears
All will have ovarian agnesis leading to ovarian failure at puberty - amenorrhea and infertility.
30 % horseshoe kidney, congenital heart defects - CoA,AS, thyroid problems
Mx = ostetrogen replacement
Kleinfelters
47xxy 1/1000 males presence of an extra x chromosomes leads to low testosterone and female bodily characteristics
PC 47xxy
Often becomes evident around puberty - gynecomastia, tall, thin, long legs, reduced muscle bulk, small testes and penis, hypogonadism
Mx = replace testosterone, CBT, counselling
Complications of Kleinfelters
Learning difficulties, osteoporosis, VTE, subfertility
Fragile X
Mutation @ FMR1 gene leads to increasing repeat sequences > 200 = fragile X, <200 = tremor, ataxia - premutation
PC fragile X
Learning difficulties, facial features - high forehead, large, ears, long face, prominent jaw. ADHD, recurrent sinus infections and connective tissue problems
FISH
Fluorescent in situ hybridisation uses probes to look for submicroscopic deletions. Therefore must know what disorders/ ares of DNA need to be targeted
Whole gene sequencing
Whole genome is examined for single nucleotide polymorphism compared to reference. Huge amounts of data can = problems but can find everything
Karyotyping
Looking at number of chromosomes down microscope to look for aneuploidy - translocations, big deletions and ring cr. Cant be used for genetic mutations smaller than chromosomal abnormalities.
Di George syndrome
22q11.2 microdeletion seen in 1/40000 live births heart malformations, improper pharyngeal pouch formation
PC Di George
underdevelopment of thyroid and parathyroid, defienciy in maturing T cells due to absence of a thymus, hypocalcemia, congenital heart defects - TOF
cleft palate, long face, small teeth, broad nose
Increased incidence of MH - schizophrenia, ADHD, autism
Prader Willi
15q11q13 gene example of genomic imprinting. Normally paternally derived gene is expressed and maternal gene is silenced. Prader willi = deletion or mutation in paternal gene/ maternal uniparental disomy
PC Prader Willi
@ birth - FTT, poor muscle tone and suck reflex
infancy - small hands, feet and eyes, hypothalamic dysfunction leads to over eating - obesity, DM, OSA, hypogonadism
Genomic imprinting
Epigenetic process that involves the methylation of DNA/histone without altering the DNA sequence
Angelman syndrome
15q11q13. Normally maternally derived with paternal chromosome being silenced. Therefore occurs due to a maternal deletion/mutation or nondisjuncture leading to inheritance of both paternal chromosomes
PC Angelmans
PC = developmental delay, ataxia, speech impairment,extremely happy demeanour short attention span, seizures,
Lyonisation
X chromosome inactivation. Dose compensation is crucial. Random X chromosome in females is inactive, can be skewed if a growth advantage is conferred.
DMD PC
2-4y/o slowly progressive, muscle weakness, waddling gait, calf hypertrophy and thigh wasting, Gower’s sign = difficulty standing up uses objects to help push up.
Progression - wheelchair bound by 20y/o, scoliosis, dilated cardiomyopathy, resp failure due to weak diaphragm
Dystrophin
Huge gene links intracellular actin and the extracellular matrix stabilising the sarcomere. In its absence the sarcomere is unstable and CK leaves, Ca2+ entry leads to muscle cell death and atrophy via water entering the mitochondria and causing them to burst. Gradually muscle is replaced with fat and fibrous tissue
DMD vs BMD
DMD - mutation severe leads to nonsense/ frame shift mutation giving no dystrophin production
BMD - misshapen dystrophin due to inframe mutation
X-linked disorders
Males cant pass the affected allele to males, daughter will always inherit the affected allele if her father is affected.
Biopsy of DMD
degeneration of muscle fibres, hypertrophy of remaining muscle fibres, scattered chronic inflammatory cells. Absent sub-sarcolemma staining
Robertsonian translocation
Two acrocenteric chromosomes join and the short arm is lost leaving only 45 Cr remaining. Despite loss of genetic material the translocation is balanced and the individual is healthy. Offspring are at risk of inheriting the unbalanced arrangement
BMD PC
Calf hypertrophy, cardiomyopathy, raised CK, life expectancy 60 y/o
Achondroplasia
AD conditon mutation in the FGFR3 gene, 80% cases are sporadic de novo mutations
PC = short stature, forehead bossing, flat nasal bridge, square hands, varus or valgus deformity, flaring at the end of long bones on X-ray
Ataxia telengectasia
AR mutation in the ATM tumour suppressor gene. Increased incidence of lymphoma, leukaemia , facial telengestasia, frequent URTI and LRTI, progressive ataxia
Von hippel lindau
AD mutation in the VHL tumour suppressor gene gives increased risk of clear cell renal cancer and phaechromocytoma
Kallmans syndrome
Congenital GnRH deficiency. PC = total anosmia, cleft palate, unilateral renal agensis, small testicles, failure to start puberty, infertility
