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Stage 4 > Inherited disease > Flashcards

Inherited disease Flashcards

1
Q

Autosomal dominance

Myotonic dystrophy
Huntington disease

A

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

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2
Q

Autosomal recessive

Sickle cell anaemia
Cystic fibrosis

A

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

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3
Q

X-linked Dominant

Fragile X

A

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

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4
Q

X-linked recessive

Duchenne muscular dystrophy
Hemophilia A

A

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

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5
Q

Penetrance

Expression

A

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

How does the disease express itself?

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6
Q
  1. Karyotype analysis
  2. FISH
  3. Array comparative genomic
    hybridization (arrayCGH)
  4. Multiplex ligation-dependent probe
    amplification (MLPA)
A
  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
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7
Q

Incomplete penetrance

A

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

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8
Q

Anticipation

A

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

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9
Q

Heterogeneity

A

One phenotype caused by a variety

of gene mutations (Limb Girdle Muscular Dystrophy)

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10
Q

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

A

Marfan
AD

Most important annual monitoring Ix = ECHO

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11
Q

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

A

Achondroplasia

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12
Q

Edwards 18 (more letters = higher number)

Patau 13

A

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

Cleft lip + multiple fingers

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13
Q

Trisomy 21

A

Downs syndrome

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

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14
Q

47XXY Klinefelters syndrome
Mechanism
Clinical
Dx

Kallmann: Low GnRH + anosmia

A

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.”

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15
Q

45X Turner syndrome
Mechanism
Clinical
Dx

A

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

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16
Q

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

A

Boy

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17
Q

Duchenne Muscular Dytrophy

A

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

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18
Q

Becker Muscular Dystrophy

A

X-linked recessive

Frame-shift mutation > Shortened dystrophin = BMD

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

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19
Q

Dystrophinopathy pathophysiology

A

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

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20
Q

Myotonic dystrophy

Features ANTICIPATION

A

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)

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21
Q

Angelman syndrome

A

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

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22
Q

Prader-Willi syndrome

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

A

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

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23
Q

An activated oncogene causes ?

A defective tumour supressor causes ?

A defective DNA repair causes ?

A

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)

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24
Q

BRCA1 cancers

BRCA2 cancers

PTEN / Cowdens

P53 Li Fraumeni

A

Breast, ovary, fallopian tube

Breast, ovary, male breast, prostate, pancreas etc

Breast, thyroid

Breast sarcoma

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25
Q

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

A

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

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26
Q

Breast cancer surveillance guidelines

A

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

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27
Q

Familial Adenomatous Polyposis

Autosomal dominant

A

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

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28
Q

Hereditary non-polyposis colon cancer
Lynch syndrome

Autosomal dominant

A

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)

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29
Q

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

A

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

30
Q

HNPCC / Lynch syndrome surveillance and risk management

A

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

31
Q

Best way to image areas not seen by colonoscopy?

A

Barium

32
Q

Peutz-Jeghers syndrome

A

AD

GI outgrowths / Hamartomatous polyps and hyperpigmented lesions on lips/oral mucosa

Increased risk of colon cancers

33
Q
  1. RET
  2. APC
  3. MSH, MLH
  4. RB1
  5. BRAF
A
  1. MEN2
  2. FAP
  3. HNPCC
  4. Retinoblastoma
  5. Melanoma
34
Q

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?

A

No screening

Even though he has an increased risk of breast Ca it is still lower than female population level risk

35
Q

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

A

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

36
Q

In breast cancer refer to secondary care if

A

Relative is male, young, or bilateral

OR
if three first degree relatives have breast cancer diagnosis

37
Q

In X linked along with fact that boys with affected X gene are always affected.

Men are never ? they are always ?

Women are usually ?

A

Carriers, affected

Carriers

38
Q

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

Allelic heterogeneity?

Loci heterogeneity?

A

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

39
Q

Explain penetrance and give an example

A

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

40
Q

Variable expression explanation and example

A

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)

41
Q

Anticipation explanation and example

A

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

Huntingtons

42
Q

What is epigenetics and examples

A

Studies genetic effects not encoded in the DNA sequence

Includes
Methylation – Essentially deactivates genes by adding a methyl group
Histone modification
Splicing

43
Q

Women who carry pathological BRCA1/2 variant- consider

A

Prophylactic double mastectomy + oophorectomy when family complete

44
Q

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

A

MEN2

Hirschsprung disease

45
Q

Colorectal cancer microsatellite and BRAF testing

Then use WHAT to determine MMR gene?

If MSI/IHC/BRAF V600E comes back abnormal

A
  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

46
Q

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

A

1/2 x 1/2 = 1/4

Fully penetrant condition

47
Q

Which two conditions feature ‘triple repeat disorder’

A

Huntingtons CAG - more repeats = earlier onset

Myotonic dystrophy CTG

Both demonstrate anticipation due to triple repeat expands each generation

48
Q

HD testing

A

If symptoms - PCR for gene mutation and FISH

49
Q

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

How?

A
  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
50
Q

Cleft lip and 6 fingers =

Limited hip abduction, overlapping fingers, tiny mouth =

A

Patau 13

Edwards 18

51
Q

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

A

Cornelia de Lange

52
Q

Short stature, normal intelligence 90%, hearing loss 50%, squints, renal anomalies-horse shoes kidney, webbed neck

Whats diagnosis and how may it occur?

A

Turners 45 X

May be due to mosaicism, deletion, ring X

53
Q

Array CGH

A

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

54
Q

G-banded chromosome testing / karyotype

A

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

55
Q

FISH

22q11

A

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

56
Q

Prader-Willi

Angelman

Which parent has the deletion

A

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

57
Q

Downs screening

A

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

58
Q

First line Ix in dysmorphic delayed children

A

aCGH

Then FISH

59
Q

Invasive test to FISH 22q11:
CVS (12w, 1% miscarriage)
Amniocentesis (16w, 0.75% misc)

May give you prob NOT absolute result, why?

A

Due to mosaicism

60
Q

High risk interventions for:

  1. Breast Ca
  2. Ovarian Ca
  3. FAP
  4. MEN2
A
  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
61
Q

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

A

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

62
Q

X linked rules

A 
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

63
Q

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

Diagnostic

A

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

64
Q

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?

A

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

65
Q

BRCA inheritance

A

Dominant

66
Q

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

A

30y

67
Q

array CGH is to detect copy number changes.

karyotype is ?

A

visualisation

68
Q

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?

A

Dominant

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

69
Q

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?

A

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
2/31/21/4 = 1/12

70
Q

FISH is not for intragenic changes it is for

CML genetic testing

A

Chromosomal microdeletions or rearrangements

Karyotype > FISH > PCR

71
Q
  1. Gonadal/Germline mosaicism
  2. Incomplete penetrance
  3. New germ-line mutation
  4. New somatic mutation
  5. Uniparental disomy
  6. Somatic mosaic
A
  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.

Stage 4 (12 decks)

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