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Flashcards in Genetic disorders Deck (45):
1

Achondroplasia

FGFR3 gene
DNA level: position 1138, G --> A
Protein level: Gly --> Arg
Comment form of short stature

2

Robertsonian translocation

Translocation between 2 acrocentric chromosomes (small short arms: 13, 14, 15, 21, 22)

3

Klinefelter syndrome

47 XXY

Chromosomal disorder
Non-Dysfunction during meiotic division

Clinical:
- hypogonadotropic hypogonadism (most common primary cause)
- eunuchoid body habitus (tall, truncal obesity)
- small testes, scant body hair, reduced libido
- rarely intellectual disability, but reduced IQ vs siblings
- beharviour: shym inc ASD, depression, anxiety
- inc DM, hypothyroidism, osteoporosis, breast ca
Low testosterone

4

Turner syndrome

45 XO (50%)
25 % mosaic 45 XO/46 XX
25% other karyotype

Chromosomal disorder

Clinical:
- short stature
- dysmorphology: web neck
- ovarian dysgenesis, infertility
- cardiac 30%: bicuspid aortic valve, coarctation of aorta, aortic stenosis
- normal intellect
- renal: urinary tract malformations 30%
- hypertension
- congenital lymphoedema

5

Autosomal dominant pedigree

Vertical transmission of phenotype
"Skipped" generation may be due to incomplete penetrance
Equal numbers of males and females affected
Most common form of inheritance
Male - male transmission
Eg. Marfan syndrome, neurofibromatosis 1

Exceptions:
De novo mutations
Incomplete penetrance
Variable expressivity
Gonadal mosaicism

6

Autosomal recessive pedigree

Horizontal appearance of phenotype
Equal numbers of males and females affected
Heterozygotes are carriers and generally healthy
Eg. CF, thalassaemia, inborn errors of metabolism

7

X-linked inheritance

Affected allele on X chromosome

Fathers (XY) pass X onto
- none of their sons (XY - as X is from mum)
- all of their daughters (XX)

Mothers (XX) pass each X onto
- half of their sons (XY or XY)
- half of their daughters (XX or XX)

Influenced by dominant vs recessive and boy vs girl

8

X-linked recessive pedigree

No father-son transmission
More affected males
All affected males' daughters are obligate carriers

Eg. haemophilia A, Duchenne muscular dystrophy, colour blidness, adrenoleukodystrophy, X-linked hypohidrotic ectodermal dysplasia, Fragile X

9

X-linked dominant pedigree

Less common clinically
Females = males
Often lethal in males, survivors are mosaic
Males are hemizygous (rather than heterozygous)

Eg. X-linked hypophosphataemic rickets, incontinentia pigmenti

10

X-inactivation

Only 1 of the 2 X chromosomes in a female is active in any one cell
= Lyonisation
Occurs randomly
All females are mosaic for X chromosome

11

Triplet repeat disorders

Allele expansion often dependent on gender of transmitting parent
Eg. myotonic dystrophy - maternal
Eg. Huntington's - paternal

12

Anticipation

Observation that particular phenotype seems to be increasing in severity in subsequent generations
Often seen in triplet repeat disorders (Eg. HD, MD)

13

Mitochondrial inheritance

Maternal inheritance
NO paternal mitochondria as sperm mitochondria are in the tail and only the head enters the egg

14

Mitochrondrial genes

37 genes, 13 encode proteins
No introns

15

Imprinting

Differential expression of a gene according to its parent of origin
- most genes expressed equally from paternal and maternal alleles
- results in monoallelic expression
- reset during gamete formation
Can silence a normal gene, i.e. creating a problem or silence a mutated gene i.e. concealing a problem
Maternal imprinting = maternal allele silenced therefore paternal gene expression

16

Prader-Willi syndrome

15q11-13
Loss of the paternally active 15q gene copy
70%: micro deletion of paternal 15q12
25%: maternal uniparental disomy 15
<1%: imprinting defect

17

Angelman syndrome

15q11-13
Loss of the maternally active 15q gene copy

18

Uniparental disomy

Arises from non-disjunction

19

Polygenic disorders

Familial clustering, but non-Mendelian patterns
Multiple genes with small effects

20

Single Nucleotide Polymorphism (SNP)

Variation in a single nucleotide that occurs at a specific position in the genome
Usually in non-coding regions

21

Retinoblastoma

RB1
Autosomal dominant

Bilateral/familial cases (AD) 92%
Unilateral/non-familial cases 10%

Associated with osteosarcoma, melanoma, soft tissue

22

Knudon's Two Hit Hypothesis

Both alleles must be crippled for total loss of function
2 hits in the same cell
- either both germline (AR) pr
- 1 germline & 1 somatic (AD)
- both recessive at cellular level (loss of all function)

23

Tumour suppressor gene

Monitor and prevent DNA replication of damaged genome
- act as cell cycle check points
- recognise DNA damage
- promote DNA repair
- initiate apoptosis (programmed cell death) if not repaired

LOSS OF FUNCTION MECHANISM

24

Proto-oncogenes

Code for gene products that regulate cell growth and regulate differentiation

GAIN OF FUNCTION MECHANISM

Single mutant allele increases malignant potential through DNA missense mutations and chromosomal translocation

25

Philadelphia chromosome

BCR-ABL
Fusion of parts of chromosomes 9, 22
t(9.22)(q34;q11)
BCR promotor causes high expression of aberrant ABL porto-oncogene --> CML
Tyrosine kinase signalling protein that is "always on"

26

MEN1

Multiple Endocrine Neoplasia
MENIN gene
Autosomal dominant

Manifestations (3 Ps):
- parathyroid adenomas 90%
- pituitary adenomas 15%
- pancreatic islet cell/GI adenomas 65%

27

MEN2A

Multiple Endocrine Neoplasia
RET gene (proto-oncogene)
Autosomal dominant

Manifestations:
- medullary thyroid cancer 90%
- phaeochromocytoma 45%
- parathyroid hyperplasia 15%

28

MEN2B

Multiple Endocrine Neoplasia
RET gene (proto-oncogene)
Autosomal dominant

Manifestations:
- medullary thyroid cancer
- phaeochromocytoma
- marfanoid body habits
- mucosal neuromas

29

Li Fraumeni syndrome

TP53 gene (tumour suppressor)
Gene product = Tumour Protein 53

Autosomal dominant
- inherit 1 abnormal allele of the gene (germline)
- 2nd allele mutates (somatic mutation) or deleted
- if 2 alleles affected, no gene to produce any functional TP53

Usually missense mutations

Clinical (SBLA)
- sarcoma
- breast (often <30, 66% HER2 amplified)
- leukaemia
- adrenal gland

30

Cowden syndrome

PTEN (phosphatase and tensin homologue) tumour suppressor gene

Autosomal dominant inheritance
Germline mutation

Clinical
- inc risk breast ca
- benign breast changes (fibrocystic disease)
- endometrial and follicular thyroid ca
- large head
- trichilemmomas (growths)
- Lhermitte Duclos (dysplastic gangliocytoma of the cerebellum)

31

FAP

Familial Adenomatous Polyposis Coli

APC tumour supressor gene
Chr 5q

Autosomal dominant
100% penetrance

Clinical:
- multiple adenomatous polyps (100s-1000s)
- often asymptomatic until cancer arises
- extracolonic manifestations: desmoid tumours (Gardner's syndrome), CHRPE (congenital hypertrophy of the retinal pigment epithelium)

Testing:
APC testing (85%)

Colonoscopy from 10yo

32

MUT-YH associated polyposis

MUTYH gene
Protein normally repairs oxidative damage to DNA
Bilallelic mutations at germline

Autosomal recessive
Mimics de novo FAP (phenocopy of FAP)

Clinical:
- multiple polyps (100s - 1000s)
- also extracolonic, eg. CHRPE (congenital hypertrophy of the retinal pigment epithelium)
- NO desmoid disease

33

Peutz-Jeghers syndrome

STK11 gene

Autosomal dominant

Clinical:
- hamartomatous polyposis
- lip, buccal, palm pigmentation
- small intestine intrasussception
- inc risk CRC and breast ca

34

Lynch syndrome

HNPCC = Hereditary nonpolyposis colorectal cancer

DNA mismatch repair gene
- MLH1
- MSH2 + 6
- PMS1 + 2

Autosomal dominant, rarely de novo

Clinical:
Most common cause of inherited colorectal ca
R sided mucinous tumours with weight loss and anaemia
Extra-colonic: endometrial, ovarian, gastric tumours

Amsterdam criteria
Early testing criteria, 3-2-1 rule
- 3 or more affected relatives with colorectal ca (on histo, not polyposis with one the 1st degree relative of the other 2)
- 2 or more generations affected
- 1 or more <50yo at diagnosis
- FAP excluded

35

Neurofibromatosis type 1

Neurofibromin 1 gene
50% de novo mutations

Autosomal dominant
Highly variable phenotype

Clinical:
- >6 cafe au lait patches
- >2 neurofibroma
- axillary freckling
- Lisch nodules on iris (melanocytic hamartomas)
- tibial pseudoarthroses

36

Neurofibromatosis type 2

NFII gene
Gene product: merlin

Autosomal dominant
50% de novo, often mosaic

Clinical:
- bilateral acoustic schwannoma 90% by 30yo
- other intracranial and spinal tumours
- polyneuropathy
- cataracts
- cutaneous tumours and plaques

37

Von Hippel Lindau Disease

VHL gene (tumour suppressor gene)
Somatic mutation often

Cinical:
- clear cell renal cancer
- neurological or retinal hemangioblastoma
- phaeochromocytoma

38

Tuberous sclerosis

"Burnsville disease"

TSC1 - 9q34 (hamartin)
TSC2 - 16p13.3 (tuberin)

Autosomal dominant
2/3 new mutations
1/3 have FHx

Highly variable expression

Clinical:
Multiple benign hamartomas of multiple organs
Epilepsy
Cognitive impairment

Tx:
mTOR inhibitors eg. serolimus

39

Friedrich ataxia

FXN - GAA repeat expansion in intron 1

Autosomal recessive

Clinical:
- clinical neurological dysfunction (cerebellum and dorsal root ganglia)
- gait and limb ataxia
- absent lower limb reflexes, up-going plantars
- post column dysfunction
- HOCM, DM

40

Huntington disease

HTT gene - exon 1 (CAG repeats)

Autosomal dominant

Anticipation (paternal inheritabce) --> greater increase in repeats
Larger repeat = earlier onset
Fully penetrant if >40 repeats

41

Duchenne muscular dystrophy

Abnormal dystrophin gene
Product: dystrophin protein

X-linked

Deletion/mutation disrupts the reading frame
Therefore no function protein

Clinical:
- proximal muscle weakness
- Gower sign (use own hands to "walk up" own body)
- mild IQ impairment
- cardiomyopathy
- onset 3yo, death 20yo

Inv:
- CK
- genetic testing
- muscle Bx: stain or dystrophin

42

Becker muscular dystrophy

Deletion/mutation is in frame
Therefore shottend semi-functional protein/milder phenotype

43

Down's

Trisomy 21 (95%)
2.5% translocation
2.5% mosaic

Clinical:
- dysmorphism
- low IQ
- hypotonia
- hearing/vision
- Alzheimer disease (eventually 100%)
- congenital heart disease 50% (VSD > endocardial cushion defect > PDA > ASD > TOF)
- hypthyroidism 30%
- GIT
- leuaemia
- occipito-atlanto-axial instability
- OSA

Inv:
- karyotype
- microarray
- FISH

44

Fragile X

X-linked
CGG triplet repeats on X chromosome (>200)

Clinical:
- low IQ (most common form of inherited mental retardation)
- behavioural problem
- physical (long face, large ears, testicular enlargement)
- seizures (20%)
- strabismus, refractory errors (30%)
- MVP

45

Marfans

FBN1 mutation
Chromosome 15

Encodes fibrillin-1, a glycoprotein component of the extracellular matrix
Ie. point mutation in a single gene

Autosomal dominant
Broad phenotype

Clinical:
- tall, long limbs, thin stature
- joint hyper mobility
- CVS: aortic dilation/dissection, AR/MR
- chest wall deformity
- lens dislocation (up)

Inv:
- clinical +/- FHx +/- FBN1