Inherited disease

Question 1

Autosomal dominance

Myotonic dystrophy
Huntington disease

Answer 1

If parent A has genes 1+2 (1 faulty) and parent B has genes 3+4 (neither faulty) then possible outcomes are 1,3 1,4 2,3 2,4 - the possibilities with a 1 in are affected, thus 50% - in autosomal dominant you only need one faulty gene

Question 2

Autosomal recessive

Sickle cell anaemia
Cystic fibrosis

Answer 2

If parent A has genes 1+2 (1 faulty) and parent B has genes 3+4 (4 faulty) then possible outcomes are 1,3 1,4 2,3 2,4 - 2 possibilities will only have 1 faulty gene (carriers), another will have none, but one will have 2 faulty genes and you need 2 in autosomal recessive, thus 25% of passing it on

Question 3

X-linked Dominant

Fragile X

Answer 3

As in autosomal dominant inheritance, only one copy of a disease allele on the X chromosome is required

Both males and females can be affected, although males may be more severely affected because they only carry one copy of genes found on the X chromosome

When a female is affected there is 1 faulty X chromosome but she must pass on one of her X chromosomes so there is always a 50% chance of passing on to offspring, regardless of sex

When a father is affected there is 1 faulty X chromosome. If they have a girl then he MUST pass on his X chromosome and thus 100% of girls will have dominant disease. but if they have a boy then he MUST have passed on his healthy Y chromosome thus no disease

Question 4

X-linked recessive

Duchenne muscular dystrophy
Hemophilia A

Answer 4

Any male with one faulty X chromosome will be affected as they only carry one X! (acts like dominant)

Carrier mother: 50% chance son will be affected (if he gets the one faulty X from mother)
50% chance daughter will be a carrier too

Affected mother:
100% of sons will be affected.
100% of daughters will be carriers

Affected father:
0% of boys are affected
100% of girls are carriers

Question 5

Penetrance

Expression

Answer 5

What proportion of individuals with a gene mutation will manifest disease?

How does the disease express itself?

Question 6

1. Karyotype analysis
2. FISH
3. Array comparative genomic
   hybridization (arrayCGH)
4. Multiplex ligation-dependent probe
   amplification (MLPA)

Answer 6

1. Chromosome changes - used for prenatal screening
2. Specific probes looking for subtle translocations on chromosomes - used in Williams syndrome - replaced by real time PCR whole exome sequencing techniques
3. Looks for loss and gain of genetic material - detects gene amplification in tumours and leukemia
4. Variation of PCR - good for prenatal diagnosis

Question 7

Incomplete penetrance

Answer 7

When an individual does not express the phenotype even though they carry the allele

Question 8

Anticipation

Answer 8

Increased severity of phenotype when passed onto the next generation (Myotonic Dystrophy / Huntington’s)

Question 9

Heterogeneity

Answer 9

One phenotype caused by a variety

of gene mutations (Limb Girdle Muscular Dystrophy)

Question 10

Tall, slim, dilatation of aortic root, ascending aorta aneurysm, lens dislocation = which disease and inheritance

Answer 10

Marfan
AD

Most important annual monitoring Ix = ECHO

Question 11

AD disease which caused by defect in FGFR3 and is sporadic 80% - Lannister from GoT

Answer 11

Achondroplasia

Question 12

Edwards 18 (more letters = higher number)

Patau 13

Answer 12

Overriding fingers + clenched fist + low set ears + ‘rocker-bottom’ feet

Cleft lip + multiple fingers

Question 13

Trisomy 21

Answer 13

Downs syndrome

Hypotonia, prominent epicathic folds, protruding tongue, Brushfields spots/whitish spots in iris, single transverse palmer crease
ASD, VSD, Fallot tetralogy, duodenal atresia

Question 14

47XXY Klinefelters syndrome
Mechanism
Clinical
Dx

Kallmann: Low GnRH + anosmia

Answer 14

Additional X chromosome

Infertility and obesity
Hypergonadotrophic hypogonadism due to loss of testosterone + gynaecomastia

Low testosterone High GnRH
Karyoype test to diagnose

“A young man with learning disabilities is tall with additional secondary sexual characteristics, enlarged breasts and small testicles and penis.”

Question 15

45X Turner syndrome
Mechanism
Clinical
Dx

Answer 15

Missing an X chromosome

Only females
Short statue, broad neck, widely spaced hypoplastic nipples, low posterior hairline, coarctation of the aorta and VSD,

HORSESHOE KIDNEY or unilateral
renal agenesis

OVARIAN AGENESIS/hypoplastic ‘streak’ ovaries
(primary amenorrhoea and infertility)

Karyoype test to diagnose

Question 16

If its X linked dominant or recessive every ? will be affected as they only have one X

Answer 16

Boy

Question 17

Duchenne Muscular Dytrophy

Answer 17

X-linked recessive

Frame-shift mutation > Nonsense mediated decay > ABSENCE of dystrophin = DMD

Gower sign (strange way of standing up), hypertrophic cardiomyopathy, behavioural issues, type 1 resp failure, live til 20s

Electromyography shows weakness is caused by destruction of muscle tissue rather than damage to nerves

Question 18

Becker Muscular Dystrophy

Answer 18

X-linked recessive

Frame-shift mutation > Shortened dystrophin = BMD

Calf hypertrophy, cardiomyopathy, limb girdle wekness, raised CK, live til 60s

Question 19

Dystrophinopathy pathophysiology

Answer 19

Dystrophin is responsible for connecting the
cytoskeleton of each muscle fiber to the
underlying basal lamina, through the
dystrophin glycoprotein complex.

Affects skeletal and cardiac muscle!

Absence of dystrophin → excess calcium
penetrates the sarcolemma →water enters
the mitochondria causing them to burst

Question 20

Myotonic dystrophy

Features ANTICIPATION

Answer 20

Autosomal dominant

CTG repeat expansion in the DMPK gene
3-37 repeats = normal
50 = cataracts
200 = cataracts, muscle weakness, myotonia
>1000 repeats = congenital form

Clue: Failure of spontaneous release of the hands following strong handshakes due to myotonia (delayed relaxation of muscles after contraction)

Question 21

Angelman syndrome

Answer 21

Lack of expression of UBE3A gene on the maternally inherited chromosome 15, while the paternal copy is imprinted and thus silenced

DNA-based methylation testing diagnostic

Neurodevelopmental disorder
Jerky movements (hand flapping)
Frequent laughter and smiling
Affinity for water

Question 22

Prader-Willi syndrome

P for lack of gene from paternal - then maternal is imprinted

Answer 22

Lack of expression of genes on the paternally inherited chromosome 15, while the maternal copy is imprinted

DNA-based methylation testing diagnostic

Slow development
Obesity - very hungry
T2DM

Question 23

An activated oncogene causes ?

A defective tumour supressor causes ?

A defective DNA repair causes ?

Answer 23

Uncontrolled proliferation (MEN2 due to RET gene)

No apoptosis (Retinoblastoma)

No repair work done (NER defect = Xeroderma Pigmentosa) (OR HNPCC or BRCA1/2 breast-ovarian)

Question 24

BRCA1 cancers

BRCA2 cancers

PTEN / Cowdens

P53 Li Fraumeni

Answer 24

Breast, ovary, fallopian tube

Breast, ovary, male breast, prostate, pancreas etc

Breast, thyroid

Breast sarcoma

Question 25

Explain PARP inhibitors and how they work for triple negative breast cancer with BRCA gene mutations

Answer 25

One characteristic of BRCA-mutated cancers is defective function of one of the major DNA damage repair pathways, the homologous recombination (HR) pathway. The original concept of the activity of PARP inhibitors was that they acted through synthetic lethality by targeting the base excision repair pathway (BER); in tumor cells with defects in a different DNA repair mechanism, disruption of both pathways led to cell death

Question 26

Breast cancer surveillance guidelines

Answer 26

National screening is with mammography 3 yearly 47-73y TP53 mutation = annual MRI from 20-49 (may have until 69) BRCA mutation = annual MRI +/- mammogram 30-49y then mammogram 50-69y Mammography should not be used if <30y OR if dense breasts so mri if high risk or maybe ultrasound if low risk

Question 27

Familial Adenomatous Polyposis Autosomal dominant

Answer 27

Present as teenager Loss of APC gene (tumour suppressor) > uncontrolled proliferation 1000s of polyps > colon ca by 40y Skin, teeth and bone abnormalities - sebaceous cysts, jaw cysts, osteoma

Question 28

Hereditary non-polyposis colon cancer Lynch syndrome Autosomal dominant

Answer 28

Present as adult DNA mismatch repair defect / "mutator pathway" Lifetime colon risk 80% Risk of ENDOMETRIAL TOO! Polyps may be absent Microsatellite instability (Impaired ability to copy repetitive DNA sequences)

Question 29

Modified Amsterdam Criteria for Hereditary non-polyposis colon cancer / Lynch syndrome

Answer 29

Modified amsterdam criteria identifies those who should have confirmatory molecular testing as about 35% of patients meeting the criteria will not have a DNA mismatch repair mutation 3 relatives affected by a related cancer colorectal, endometrial, ovarian, small intestine, stomach transitional cell, At least 2 successive generations affected One colorectal case before age 50 FAP is excluded

Question 30

HNPCC / Lynch syndrome surveillance and risk management

Answer 30

Screening: Regular bowel screening with colonoscopy at least 2 yearly from age 25 Females should be referred for gynaecological assessment Risk management: Colectomy if very high risk or >1 colon cancer Hysterectomy, oophrectomy Long-term low dose aspirin (75mg od) Significant reduction in polyp burden

Question 31

Best way to image areas not seen by colonoscopy?

Answer 31

Barium

Question 32

Peutz-Jeghers syndrome

Answer 32

AD GI outgrowths / Hamartomatous polyps and hyperpigmented lesions on lips/oral mucosa Increased risk of colon cancers

Question 33

1. RET 2. APC 3. MSH, MLH 4. RB1 5. BRAF

Answer 33

1. MEN2 2. FAP 3. HNPCC 4. Retinoblastoma 5. Melanoma

Question 34

Mr Banks is a 40 year old male with a known BRCA1 mutation. He is very concerned about the risk of breast cancer as his mother and sister have both died from the condition. What breast cancer screening is advisable at present?

Answer 34

No screening Even though he has an increased risk of breast Ca it is still lower than female population level risk

Question 35

Joseph is a 40 year old man with colorectal cancer. He has just been diagnosed with Lynch syndrome. Which of the following is correct? Suspected cases should be scored using the Paris criteria Patients with Lynch syndrome should be offered colonoscopy screening from age 30y. Joseph’s biological family members have the same risk of colorectal cancer as the general population Lynch syndrome is characterised by hundreds to thousands of intestinal polyps Microsatellite instability is a defining feature of Lynch syndrome

Answer 35

A amsterdam not paris B should be from 25y C have an increased risk D no may have polyps but is less than 100 E will get microsatellite instability due to MMR defect

Question 36

In breast cancer refer to secondary care if

Answer 36

Relative is male, young, or bilateral OR if three first degree relatives have breast cancer diagnosis

Question 37

In X linked along with fact that boys with affected X gene are always affected. Men are never ? they are always ? Women are usually ?

Answer 37

Carriers, affected Carriers

Question 38

Genetic heterogeneity is how same phenotypes can occur despite different genetic mechanisms Allelic heterogeneity? Loci heterogeneity?

Answer 38

Different mutations at the same loci causes similar phenotype Mutations at different loci can cause similar phenotype Allele – A different version of the same gene (e.g. blue vs brown eyes) Locus – Specific point on a chromosome (Can be the site of a particular gene) For example Long QT syndrome whereby various genes can cause the same condition

Question 39

Explain penetrance and give an example

Answer 39

The proportion of people who carry the allele that express traits of the mutation Complete = 100% of people express the phenotype Huntingtons Incomplete = <100% of people express the phenotype Retinoblastoma

Question 40

Variable expression explanation and example

Answer 40

Expressivity measures the EXTENT to which a genotype exhibits its phenotypic expression Thus people with the same mutation can have different symptoms and severity Neurofibromatosis Marfan (can be de novo)

Question 41

Anticipation explanation and example

Answer 41

Observation of increasingly severe, earlier onset of a genetic trait in succeeding generations Huntingtons

Question 42

What is epigenetics and examples

Answer 42

Studies genetic effects not encoded in the DNA sequence Includes Methylation – Essentially deactivates genes by adding a methyl group Histone modification Splicing

Question 43

Women who carry pathological BRCA1/2 variant- consider

Answer 43

Prophylactic double mastectomy + oophorectomy when family complete

Question 44

RET gene is activated in adults causing ? and inactivated in embryogenesis causing ?

Answer 44

MEN2 Hirschsprung disease

Question 45

Colorectal cancer microsatellite and BRAF testing Then use WHAT to determine MMR gene? If MSI/IHC/BRAF V600E comes back abnormal

Answer 45

1. MSI high = maybe Lynch then check BRAF V600E as this is rare in Lynch 2. MSI low = sporadic colorectal ca Immunohistochemistry Abnormal = 2 yearly from 25

Question 46

If Janet grandad has Huntingtons then what are the chances of her having huntingtons, if we dont know if her father has it Why is huntington testing to important

Answer 46

1/2 x 1/2 = 1/4 Fully penetrant condition

Question 47

Which two conditions feature 'triple repeat disorder'

Answer 47

Huntingtons CAG - more repeats = earlier onset Myotonic dystrophy CTG Both demonstrate anticipation due to triple repeat expands each generation

Question 48

HD testing

Answer 48

If symptoms - PCR for gene mutation and FISH

Question 49

A pedigree showing an individual diagnosed with a presumed genetic condition where no one else in the family appears to be affected. How?

Answer 49

1. This could be a new (de novo) mutation 2. This could be a dominant condition with incomplete penetrance 3. The condition could be dominantly inherited but variably expressed (i.e. very mild phenotype in one parent) 4. This could be a recessive condition 5. If affected individual is male, consider an X linked pattern of inheritance 6. Other possibilities exist e.g. an imprinted disorder, parent has mosaicism which includes germline cells 7. The condition may be non-genetic

Question 50

Cleft lip and 6 fingers = Limited hip abduction, overlapping fingers, tiny mouth =

Answer 50

Patau 13 Edwards 18

Question 51

Diagnosis on characteristic facial features- thin monobrow, thin vermillion border, pinched up nose, long filtrum, long eyelashes 35% due to de novo mutation in NIPBL

Answer 51

Cornelia de Lange

Question 52

Short stature, normal intelligence 90%, hearing loss 50%, squints, renal anomalies-horse shoes kidney, webbed neck Whats diagnosis and how may it occur?

Answer 52

Turners 45 X May be due to mosaicism, deletion, ring X

Question 53

Array CGH

Answer 53

1st line if NOT recognisable diagnosis ie trisomy Examines whole genome for loss/gain of genetic mutation Can't detect trisomy! Not good for mosaicism or balanced chromosome rearrangements ie reciprocal translocations

Question 54

G-banded chromosome testing / karyotype

Answer 54

Used in diagnosis of monosomies, trisomies, translocations and large deletions and insertions

Question 55

FISH 22q11

Answer 55

Follow up karyotype with FISH IE know there is del/insert- but don’t know where it is > FISH detects location MICROdeletions + insertions and reciprocal translocations

Question 56

Prader-Willi Angelman Which parent has the deletion

Answer 56

Paternal deletion (P for P) - hungry MATernal deletion (female = angel) - laughter The paternal gene is always silenced in Angelman and vice versa for Prader-Willi

Question 57

Downs screening

Answer 57

Maternal age + Nuchal thickness (USS-12w) + maternal serum (AFP, hCG, Abs)

Question 58

First line Ix in dysmorphic delayed children

Answer 58

aCGH Then FISH

Question 59

Invasive test to FISH 22q11: CVS (12w, 1% miscarriage) Amniocentesis (16w, 0.75% misc) May give you prob NOT absolute result, why?

Answer 59

Due to mosaicism

Question 60

High risk interventions for: 1. Breast Ca 2. Ovarian Ca 3. FAP 4. MEN2

Answer 60

1. DNA testing ie BRCA or mastectomy 2. Surveillance with USS + CA125 OR bilateral salpingo-ooporectomy 3. Colectomy in late teens 4. Remove thyroid as young as 1y

Question 61

Parents want baby, father has sister that died of CF - wants to know chances of having baby with CF?

Answer 61

If sister tt then both parents carried recessive, thus Fathers genotype TT (1/3) or Tt (2/3) and general population risk is (1/20) So risk of both being carriers is 2/3 * 1/20 THEN risk of affected child with two carriers is 1/4 SO 1/4 * 2/3 * 1/20 = 1/120

Question 62

X linked rules

Answer 62

``` Carrier females have: a 1 in 4 chance of an affected male a 1 in 4 chance of a normal male a 1 in 4 chance of a carrier daughter a 1 in 4 chance of a normal daughter ``` Affected males cannot pass the disorder to their sons. All of an affected male’s daughters will inherit the mutation

Question 63

Big calves and Gowers sign (crawl hands up legs to stand up) = Diagnostic

Answer 63

Duchenne uscular dystrophy Raised CK and abnormal LFTs, muscle wasting and weakness + intellect and behavioural issues Muscle biopsy (with immunostaining for dystrophin) 1st line Multiplex ligation probe amplification MLPA and PCR Often no FH as high rate of de novo mutation Becker is the milder version

Question 64

A lady who had breast cancer aged 45 and a family history of breast cancer undergoes BRCA testing. The lab find a variant of uncertain significance in BRCA 1. How should you proceed?

Answer 64

Consider segregation studies in the family but do not base management decisions on this result as things stand

Question 65

BRCA inheritance

Answer 65

Dominant

Question 66

BRCA1 (worse for breast ca than brca2)breast cancer screening MRI from

Answer 66

30y

Question 67

array CGH is to detect copy number changes. | karyotype is ?

Answer 67

visualisation

Question 68

A 52-year-old lady with a definite clinical diagnosis of Marfan syndrome attended the Genetics Clinic.  Molecular genetic testing of her Fibrillin 1 gene did not reveal any known pathogenic mutations.  Her two children, aged 23 and 25 years old, also attended the appointment. HOW WOULD YOU BEST ADVISE HER CHILDREN?

Answer 68

Dominant They should be examined for signs of Marfan syndrome and have an echocardiogram.

Question 69

Individual 2 is shown to be a carrier of cystic fibrosis. Individual 3 does not have cystic fibrosis. What is the risk that the baby born as a result of pregnancy 5 will have cystic fibrosis?

Answer 69

Individual 3 has an affected sibling so we assume that their parents were both carriers, and since we know 3 doesnt have CF then the only option are 1/3 unaffected, 2/3 carrier, so their risk of being a carrier is 2/3 Individual 2 is a known carrier and so we assume that only one of her parents was a carrier and so each child would have 1/2 chance of being a carrier, so their siblings risk is 1/2 And if both are carriers then there is a 1/4 chance of being affected so 2/3*1/2*1/4 = 1/12

Question 70

FISH is not for intragenic changes it is for CML genetic testing

Answer 70

Chromosomal microdeletions or rearrangements Karyotype > FISH > PCR

Question 71

1. Gonadal/Germline mosaicism 2. Incomplete penetrance 3. New germ-line mutation 4. New somatic mutation 5. Uniparental disomy 6. Somatic mosaic

Answer 71

1. Some sperm/oocytes carry a mutation but the rest are normal thus two 'unaffected' parents can have 2 affected children 2. All cells carry the mutation but it may not manifest in all patients 3. Parents would be affected as well as children 4. Random 5. Chromosomes from only one parent, a bit like genomic imprinting 6. All cells in the patient have the same genes but some are expressed and some are not. Heterochromia (one blue eye and 1 brown eye) is an example.