Week 02 Genetics

• AD
• Vertical pattern of inheritance
• passed from father to son
• Disease expression in heterozygotes
• 50% risk to offspring
• variable expressivity
• incomplete penetrance
• e.g. Achondroplasia [short stature]

• Genetic modifier variant
• Other genes that affect severity of phenotype
• [FGFR2 Mt effects BrCa2 penetrance]

• AR
• Only affected if have 2 copies of affected gene, 1 copy = carrier
• Horizontal pattern [in same sib-ship]
• only expressed in homozygotes/ compound heterozygotes [2Mt in same gene]
• Lower risk of TMx to children [n.b. carrier rate]
• More constant within family
• Consaguinuity ^^ risk [double line in pedigree]

• Never Male → male TMx
• Females are carriers [obligate = circle w dot]
• Features
• Knights move inheritance
• All daughters carriers
• occaisional manifesting carriers [skewed x-inactivation]

• Looks like AD, but no Male → Male TMx
• Vertical Pattern
• all daughters affected
• F:M 2:1

• Y-linked inheritance [Holandric]
• Mt in sex det region Y [SRY] - male infertility

• Pseudo-Autosomal Inheritance
• similarity of X & Y on PAR of Xp, escape X inactivation, appears AD

• Pseudo-Dominant Inheritance
• AR inherited, but ^^ carrier freq appears AD [e.g. gilbert syndrome]

• Mosaicism
• Somatic → not affecting gonads e.g. Mcune-Albright syndrome [skin & hormone Probs]
• Gonadal → Mt in gonads

• Imprinting Disorders
• Gene expressed from just 1 allele due to methylation 'imprinting' of DNA
• e.g. angelman syndrome, prader willi syndrome [hypotonia, overeat, LDs]

• Mitochondrial Inheritance
• smaller genome [37] no introns
• maternal inheritance only
• often affect muscle, brain & eyes

Huntingtons Disease → AD w genetic anticipation

• CF
• adult onset [30-50yo]
• progressive chorea [involuntary movements → weight loss]
• dementia
• psych symtoms
• Poor prognosis [death in 17y] worse if juvenile onset
• Nueurpathology → atrophy of small neurones [caudate & petumen]
• Dx → clinical & FH, Imaging & DNA test to confirm

• Molecular Basis
• CAG [glutamine] reps in HD gene → num of repeats det severity [>39 = phenotype]
• Shows genetic anticipation → ea gen CAG-r ^^ esp if paternal TMx
• CAG → polyglutamine tract [huntingtin]→ insoluable, aggregates → neurotixic → symptoms

Myotonic Dystrophy → AD w anticipation

• CF
• progressive muscle weakness
• myotonia [grip to hard]
• susceptible to → DM, cardiac conduction defects
• Congenital → floppy baby, resp probs, poss neonatal death

• Molecular Basis
• CTG repeat on DMPK [Affected 50-2000 rpts]
• abnormal mRAN indirect toxic effect on splcing of other genes → Cl ion channels → myotonia
• Shows anticipation, worse if maternal TMx

Cystic Fibrosis → AR ^^carrier freq

• CF
• Bronchiectusis & obstructive lung disease
• Meconium Ileus [obstruction at birth]
• Pancreas → exocrine & endocrine failure

• Molecular Basis
• CFTR Mt → defective Cl channel
• ^thickness of secretions
• screen neonates on guthrie card [imunoreactive trypsin - IRT]

Haemochromatosis → AR compound heterozygotes

• CF
• Progressive Fe accumulation
• Untreated → DM, cirrhosis, arthropathy, cardiomyopathy, HCC
• Tx → therapeutic venesection

• Molecular basis
• HFe on C6 → C282Y & H63D [milder] Mt
• Clinical in C282Y homozygotes & C282Y/ H63D compound heterozygotes

DMD → XL-R inheritance

• CF
• onset ~3y, wheelchair ~12y
• Progressive muscle weakness [voluntary intially]
• Toe walking, Gowers Sign [stand up using hands]

• Molecular Basis
• out of frame deletion in Xp21 [no dystrophin produced]
• Dystrophin links F-actin w dystroglycan [structural intact during contraction]
• CK leaks out of muscles

• BMD
• in frame deletion, some dystrophin made
• onset ~11y
• Wheelchair late/not at all

NF1 → AD inheritance, variable expression

• CF
• Cafe au lait spots & neurofibromas → teenage
• Iris lisch nodules → adults [dont affect vision]
• General → short stature w macrocephaly
• ~mild LDs
• Complications → scoliosis, patho tibial #, HBP, tumours [phaechromocytoma, sarcoma, optic pathway gliomas, CNS tumours]

• Genetics
• Mt of GTPase regulating RAS [normal] in growth factor receptor transduction p way
• in NF1 RAS linked to GTP → ongoing activation of pathway →tumours

Fragile X → XL-R genetic anticipation

• CF
• Severe phenotype in males
• long face, large ears, enlarged testes
• LDs

• Genetics
• CCG repeats in FMR1 gene
• Phenotype → >200rpts, CF present 50% carrier fem = affected
• Pre-Mt → 55-200rpts, No LDs, but can get ataxia/ tremor

• Trisomy 21
• causes DS, young parents, low risk [but more births]
• 14-21 translocation = ^^risk
• CF → heart malformations, hypothyroidism, single palmar crease

• Edwards Syndrome → trisomy 18
• CF → small chin, clenched hands overlapping fingers, heart defects, severe LDs

• Trisomy 13 → Patua Syndrome
• CF → congenital heart defects, extra pinky finger, severe LD. ^^neonatal mortality

• Tumour Supressor Gene [TSG]
• inhibit progression through cell cycle e.g. p53, NF1
• promote apoptosis e.g. p53, BAX
• Loss of function Mt
• Recessive → req 2 Mt

• Proto-oncogene
• produce proteins that stimulate cell cycle
• Activated → oncogenes
• dominant
• Mt = gain of function

• Oncogene
• gene that has potential to cause cancer

Loss of function Mt → Mt causes gene to stop doing something e.g. TSG dont suppress tumours

Gain of function → Mt causes gene to start doing something e.g. protooncogenes become oncogenes

• Functions
• Caretake genes
• repair via homologous recombination of double strand breaks → good, low error
• if Mt dont work need to use → NHEJ

• NHEJ
• Non-homologous end joining → repair double strand breaks, not as good →mistakes → cancer

• Hereditary Nonpolyposis colorectal Ca
• AD inherited Mt in MSH1 & 2 [mismatch repair system genes MMR]
• CF → few polyps [<10] +/- uterus/stomach/ovarian Ca
• Males → 80-90% risk CRCa
• Females → 40% CRCa

• Screening
• moderate risk → 1st degree relative, <45yo, colonoscopy ea 5yr 55-75
• High risk [MMR Mt present] 2 yearly colonoscopy, 25-30yo

• Familial Adenomatous Polyposis
• AD inherited Mt TSG
• Congenital hypertrophy of retinal pigment [eyes]
• >100 polyps in bowel

• Implications?
• Bowel screening from age 11
• ^^risk of colon Ca

• ARMS → amplifications refractory Mt System [Allele specific PCr
• uses primers that match Mt/Wt
• Works like PCR
• No amplification of sequence if primers dont match
• shows presence of known Mt

• Quantitive Flourescant PCR
• DNA markers from sample are amplified + tagged w flourescant
• Amount of DNA measured by electrophoreisis
• Used to detect aneuploidies [abn num of chromosomes]

• Pts Clinical Hx → Age of onset, progression?
• FH? → consaguinuity, miscarriage, still births?
• Examination
• Dysmorphic Features?
• head to toes

• Normal Growth
• Height
• Occipital-frontal circumference

• Investigations
• Biochem → DNA [EDTA tube] Chromosomes [Heparinised tube]

Genetic screening →whole pop, not v invasive, ?specificity

• Downs Syndrome → 1/700pregnancies
• 1st trimester → CUBs [combined U/S & biochem]
• hCG ^, PAPPA low, U/S → nuchal translucency
• 2nd Trimester → quadruple biochem
• AFP &UE3 = low
• ^hCG & Inhibin-A

• Guthrie Card → heel blood spot
• PKU
• Congenital Hypothyroidism
• Cystic Fibrosis
• Sickle Cell Disease

• Tay-sachs disease → jewish pop, pre-regnancy
• Thalassaemia → marriage prereq in some countries

• Clearly defined disorder
• appreciable frequency
• advantage to early diagnosis
• ^specificity [few false positive, only shows what it tests for]
• ^sensitivity [ few false negatives, always gets the answer right]
• Benefits > costs