Genetics

Question 1

Genetic abnormality that most commonly caused Downs Syndrome?

Answer 1

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

Question 2

COL4A5 gene

Answer 2

X-linked transmission in Alport Syndrome

Question 3

UMOD gene

Answer 3

Autosomal dominant tubulointerstitial kidney disease (ADTKD)

ADTKD due to UMOD mutations characterised by gout occurring at an early age

Question 4

HNF1B

Answer 4

Hepatocyte nuclear factor 1 beta
ADTKD due to HNF1B - renal cysts, maturity onset diabetes of youth, hyperuricemia, hypomagnesemia, deranged LFTs and renal anomalies

Question 5

MUC1

Answer 5

Mutation causes subtype of ADTKD
Progressive CKD (no cysts)
Autosomal dominant

Question 6

Fabry disease

Answer 6

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

Question 7

BMPR2

Answer 7

Bone morphogenic protein receptor

Common in heritable pulmonary arterial hypertension

Question 8

Robertsonian translocation

Answer 8

Translocation between 2 acrocentric chromosomes (13, 14, 15, 21, 22)

Question 9

Klinefelter Syndrome

Answer 9

47, XXY
Most common cause of primary male hypogonadism
Low testosterone
Infertility, incomplete virilisation, gynecomastia
Tall
Learning difficulties, emotionally immature, shy

Question 10

Turner Syndrome

Answer 10

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

Question 11

Autosomal dominant

Answer 11

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

Question 12

Autosomal recessive

Answer 12

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

Question 13

X linked recessive

Answer 13

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

Question 14

Methylation

Answer 14

Promoter regions are CpG rich

IF methylated the promoter region = turn off the gene (transcriptional silencing)

Question 15

Gene expression is influenced by?

Answer 15

Conformation of chromatin
Methylation of DNA
Availability of transcription factors

Question 16

Imprinting

Answer 16

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

Question 17

Prader-Willi Syndrome

Answer 17

Imprinting disorder - loss of the paternally active 15q gene copy

Hypotonia, hyperphagia, obesity, short stature, moderate ID, hypogonadism

Question 18

Angleman Syndrome

Answer 18

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

Question 19

FISH

Answer 19

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

Question 20

Next-generation sequencing

Answer 20

DNA sequencing of whole genome / exome
Analyse multiple genes simultaneously
Cannot detect triple repeats or methylation defects

Question 21

Pharmacogenetics - Warfarin

Answer 21

Cytochrome P450 (CYP2C9)

Question 22

Pharmacogenetics - Tamoxifen

Answer 22

Cytochrome P450 (CYP2D6)

Question 23

Karyotype

Answer 23

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)

Question 24

Comparative Genomic Hybridization

Answer 24

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

Question 25

Single nucleotide polymorphism array

Answer 25

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

Question 26

Sanger sequence

Answer 26

Exact DNA sequence of bases of a gene Can detect single gene mutations E.g. Noonan (PTPN11), NF1, Marfan (FBN1)

Question 27

PCR

Answer 27

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

Question 28

Triple repeat disorders

Answer 28

``` Fragile X - CGG Huntington Disease - CAG Spinocerebellar Ataxia - CAG Friedrich Ataxia - GAA Myotonic Dystrophy - CTG ```

Question 29

Multiplex Ligation-dependent Probe Amplification

Answer 29

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

Question 30

Li Fraumeni Syndrome

Answer 30

``` SBLA: Sarcoma, Breast (HER2 positive),Leukaemia, Adrenal gland TP53 - tumor suppressor gene Inherited autosomal dominant disorder Cancer diagnosis at a young age Highly penetrant ```

Question 31

Cowden Syndrome

Answer 31

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

Question 32

Von Hippel Lindau Disease

Answer 32

VHL tumor suppressor gene Clear cell renal cancer Sequale from neuro or retinal haemangioblastoma Phaeochromocytoma

Question 33

Neurofibromatosis Type 1

Answer 33

``` 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

Question 34

Neurofibromatosis Type 2

Answer 34

``` 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

Question 35

Beckwith Wideman Syndrome

Answer 35

``` Loss of maternal 11p15 gene Overgrowth disorder Macrosomia Macgroglossia Embryonal malignancies ```

Question 36

Russell Silver Syndrome

Answer 36

Loss of paternal 11p15 genes Short stature IUGR Triangular face

Question 37

Tuberous Sclerosis

Answer 37

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)

Question 38

Friedrich Ataxia

Answer 38

Autosomal dominant Progressive neurological dysfunction: cerebellum & dorsal root ganglia Absent lower limb reflexes, up going planters Posterior column dysfunction Hypertrophic cardiomyopathy, Diabetes

Question 39

Duchenne Muscular Dystrophy

Answer 39

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

Question 40

Marfans

Answer 40

``` Diagnosis in absence of FHx Aortic root enlargement and 1 of the following - ectopica lentils - pathogenic FBN1 variant - Systemic score >7 ```

Question 41

Homoplasmy

Answer 41

All of the mitochondrial DNA is affected

Question 42

Achondroplasia

Answer 42

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