Genetics Flashcards
Genetic abnormality that most commonly caused Downs Syndrome?
Nondisjunction = error in cell division where the chromosomes fail to separate during cell division. Meiotic disjunction will result in the gamete carrying this abnormality and further resulting in trisomy 21
COL4A5 gene
X-linked transmission in Alport Syndrome
UMOD gene
Autosomal dominant tubulointerstitial kidney disease (ADTKD)
ADTKD due to UMOD mutations characterised by gout occurring at an early age
HNF1B
Hepatocyte nuclear factor 1 beta
ADTKD due to HNF1B - renal cysts, maturity onset diabetes of youth, hyperuricemia, hypomagnesemia, deranged LFTs and renal anomalies
MUC1
Mutation causes subtype of ADTKD Progressive CKD (no cysts) Autosomal dominant
Fabry disease
X-linked disorder
Little or no functional alpha-Gal A enzyme activity
- severe neuropathic or limb pain
- telangiectasias and angiokeratomas (hip, groin, periumbilical)
- GI symptoms: abdo pain, N / V / D
- Corneal opacities
- Renal manifestations e.g. proteinuria
- Cardiac: LVH, myocardial fibrosis, heart failure, valve abnormalities
- TIA / stroke
BMPR2
Bone morphogenic protein receptor
Common in heritable pulmonary arterial hypertension
Robertsonian translocation
Translocation between 2 acrocentric chromosomes (13, 14, 15, 21, 22)
Klinefelter Syndrome
47, XXY
Most common cause of primary male hypogonadism
Low testosterone
Infertility, incomplete virilisation, gynecomastia
Tall
Learning difficulties, emotionally immature, shy
Turner Syndrome
45,X - don’t have 2 X chromosome in female
Web neck
Ovarian dysgenesis, infertility
Cardiovascular defects: bicuspid aortic valve, coarctation of the aorta
Normal intellect
Autosomal dominant
Disease results from mutation in one copy of gene / allele (heterozygous)
If one parent has the disease, 50% chance child inherits the gene
E.g. NF; Marfans
Autosomal recessive
Disease results from mutation in both copies of gene / allele (homozygotes)
If both parents are carriers, 25% chance child inherits 2 copies of the gene
E.g. CF, Thalassa is
X linked recessive
Absence of father-son transmission
Affected males much more common
Females rarely affected
E.g. Haemophilia A, duchenne muscular dystrophy, colour blindness, adrenoleukodystrophy, Fragile X
Methylation
Promoter regions are CpG rich
IF methylated the promoter region = turn off the gene (transcriptional silencing)
Gene expression is influenced by?
Conformation of chromatin
Methylation of DNA
Availability of transcription factors
Imprinting
Involves parental specific methylation of CpG-rich domains and modification of of his tone proteins
Is the epigenetic marking of a gene based on its parental origin and results in monoalleic expression
Maternal imprinting = maternal silencing, paternal gene expression
Prader-Willi Syndrome
Imprinting disorder - loss of the paternally active 15q gene copy
Hypotonia, hyperphagia, obesity, short stature, moderate ID, hypogonadism
Angleman Syndrome
Loss of maternally active 15q gene copy Paternal uniparental disomy Imprinting defect (q12) Large deletion on maternally inherited chromosome 15 Angleman Gene = UBE38
Severe intellectual disability, unsteady gait, epilepsy
FISH
Fluorescent tagged DNA probes for specific target
Detect presence/absence of specific DNA sequences on Chromosomes
Locus specific
Requires locus specific hypothesis
Takes 24 hours
E.g. trisomy
Next-generation sequencing
DNA sequencing of whole genome / exome
Analyse multiple genes simultaneously
Cannot detect triple repeats or methylation defects
Pharmacogenetics - Warfarin
Cytochrome P450 (CYP2C9)
Pharmacogenetics - Tamoxifen
Cytochrome P450 (CYP2D6)
Karyotype
Visually analyses whole chromosomes
Detects aneuploidy, large chromosomal imbalances and unbalanced translocations
Cells arrested in metaphase - chromosomes stained
Takes 10 days
E.g. looking at world from outer space…New Zealander has disappeared (e.g. Turner syndrome)
Comparative Genomic Hybridization
Compare DNA from two sources (test and control)
Looks at gains / losses of DNA; also looks at copy numbers variations
I.e. Google earth map is a jigsaw puzzle- see if any pieces are missing or duplicated
E.g. Trisomy 21, 22q11
Single nucleotide polymorphism array
Variation in a single nucleotide at a specific locus
Can detect copy number abnormalities (microdeletions / microduplications), allelic imbalance
E.g. loss of heterozygosity e.g. uniparental disomy in Angelman
Mutated copy of tumor suppressor gene in cancer
MAY get results of unknown significance
Sanger sequence
Exact DNA sequence of bases of a gene
Can detect single gene mutations
E.g. Noonan (PTPN11), NF1, Marfan (FBN1)
PCR
Used for amplification of sequence of interest
Heat dsDNA - separates strands
Oligonucleotide primer binds to start of DNA sequence of interest
Primer helps the DNA polymerase get started
Polymerase reads down the DNA sequence - adds complementary base pairs to form complementary sequence
Triple repeat disorders
Fragile X - CGG Huntington Disease - CAG Spinocerebellar Ataxia - CAG Friedrich Ataxia - GAA Myotonic Dystrophy - CTG
Multiplex Ligation-dependent Probe Amplification
Gene exon
Locus specific hypothesis
Modified PCR amplification
Each amplification product has a unique length
Amplification products separated by electrophoresis
Reflects the relative copy number of target sequences
Tests for deletions and duplications of any gene
Li Fraumeni Syndrome
SBLA: Sarcoma, Breast (HER2 positive),Leukaemia, Adrenal gland TP53 - tumor suppressor gene Inherited autosomal dominant disorder Cancer diagnosis at a young age Highly penetrant
Cowden Syndrome
PTEN (phosphate and tensin homologous) tumor suppressor gene
Autosomal dominant inheritance of a germ line mutation
Breast cancer, bending breast changes, endometrial and follicular thyroid cancer, microcephaly
Von Hippel Lindau Disease
VHL tumor suppressor gene
Clear cell renal cancer
Sequale from neuro or retinal haemangioblastoma
Phaeochromocytoma
Neurofibromatosis Type 1
Requires two or more of: >6 cafe au lait patches >2 neurofibromas OR 1 plexiform neurofibroma Axillary and / or inguinal freckling >2 Lisch nodules on iris Optic glioma Tibial pseudo arthritis 1sr degree relative with NF
Gene: Neurofibromin 1 (AD)
Highly variable phenotype
Autosomal dominant
Neurofibromatosis Type 2
Bilateral acoustic schwannoma Intracranial and spinal Timor’s: meningioma, neurofibromas, Schwannoma, Glioma Polyneuropathy Cataracts Cutaneous tumors and plaques
Genetics: mutation in NF2 gene (codes for Merlin) Autosomal Dominant
Beckwith Wideman Syndrome
Loss of maternal 11p15 gene Overgrowth disorder Macrosomia Macgroglossia Embryonal malignancies
Russell Silver Syndrome
Loss of paternal 11p15 genes
Short stature
IUGR
Triangular face
Tuberous Sclerosis
Autosomal dominant
Abnormal TSC 1 or 2 (tumor suppressor gene)
Multiple benign hamartomas of multiple organs
Skin: hypopigmented lesions, facial angiofibroma, shagreen patches, forehead fibrous plaques
Brain: seizures, ID, tubers, subependymal nodules
Kidney: renal angiomyolipotomata
Heart: cardiac rhabdomyomas
Rx: mTOR inhibitors (mTOR activated by mutations in TSC1 and 2)
Friedrich Ataxia
Autosomal dominant
Progressive neurological dysfunction: cerebellum & dorsal root ganglia
Absent lower limb reflexes, up going planters
Posterior column dysfunction
Hypertrophic cardiomyopathy, Diabetes
Duchenne Muscular Dystrophy
Deletion / mutation disrupts the reading frame = no functional protein (dystrophin)
Proximal muscle weakness - Gower sign, calf pseudohypertrophy
Dystrophin also in heart/brain = cardiomyopathy; IQ impairment
Becker muscular dystrophy = deletion / mutation is ‘in frame’ resulting in a shortened semi-functional protein / milder phenotype
Marfans
Diagnosis in absence of FHx Aortic root enlargement and 1 of the following - ectopica lentils - pathogenic FBN1 variant - Systemic score >7
Homoplasmy
All of the mitochondrial DNA is affected
Achondroplasia
Autosomal dominant disorder associated with short stature
Mutation in Fibroblast Growth Factor Receptor 3 (FGFR-3) gene
Short limbs, short fingers
Large head with frontal bossing
Midface hypoplasia with a flattened nasal bridge
