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Genetics > Genetic disorders > Flashcards

Genetic disorders Flashcards

1
Q

Achondroplasia

A

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

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2
Q

Robertsonian translocation

A

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

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3
Q

Klinefelter syndrome

A

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

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4
Q

Turner syndrome

A 
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
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5
Q

Autosomal dominant pedigree

A

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
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6
Q

Autosomal recessive pedigree

A

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

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7
Q

X-linked inheritance

A

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

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8
Q

X-linked recessive pedigree

A

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

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9
Q

X-linked dominant pedigree

A

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

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10
Q

X-inactivation

A

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

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11
Q

Triplet repeat disorders

A

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

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12
Q

Anticipation

A

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

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13
Q

Mitochondrial inheritance

A

Maternal inheritance

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

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14
Q

Mitochrondrial genes

A

37 genes, 13 encode proteins

No introns

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15
Q

Imprinting

A

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

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16
Q

Prader-Willi syndrome

A 
15q11-13
Loss of the paternally active 15q gene copy
70%: micro deletion of paternal 15q12
25%: maternal uniparental disomy 15
<1%: imprinting defect
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17
Q

Angelman syndrome

A

15q11-13

Loss of the maternally active 15q gene copy

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18
Q

Uniparental disomy

A

Arises from non-disjunction

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19
Q

Polygenic disorders

A

Familial clustering, but non-Mendelian patterns

Multiple genes with small effects

20
Q

Single Nucleotide Polymorphism (SNP)

A

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

21
Q

Retinoblastoma

A

RB1
Autosomal dominant

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

Associated with osteosarcoma, melanoma, soft tissue

22
Q

Knudon’s Two Hit Hypothesis

A

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
Q

Tumour suppressor gene

A

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
Q

Proto-oncogenes

A

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
Q

Philadelphia chromosome

A

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
Q

MEN1

A

Multiple Endocrine Neoplasia
MENIN gene
Autosomal dominant

Manifestations (3 Ps):

  • parathyroid adenomas 90%
  • pituitary adenomas 15%
  • pancreatic islet cell/GI adenomas 65%
27
Q

MEN2A

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

Manifestations:

  • medullary thyroid cancer 90%
  • phaeochromocytoma 45%
  • parathyroid hyperplasia 15%
28
Q

MEN2B

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

Manifestations:

  • medullary thyroid cancer
  • phaeochromocytoma
  • marfanoid body habits
  • mucosal neuromas
29
Q

Li Fraumeni syndrome

A 
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
Q

Cowden syndrome

A

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
Q

FAP

A

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
Q

MUT-YH associated polyposis

A

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
Q

Peutz-Jeghers syndrome

A

STK11 gene

Autosomal dominant

Clinical:

  • hamartomatous polyposis
  • lip, buccal, palm pigmentation
  • small intestine intrasussception
  • inc risk CRC and breast ca
34
Q

Lynch syndrome

A

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
Q

Neurofibromatosis type 1

A

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
Q

Neurofibromatosis type 2

A

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
Q

Von Hippel Lindau Disease

A 
VHL gene (tumour suppressor gene)
Somatic mutation often

Cinical:

  • clear cell renal cancer
  • neurological or retinal hemangioblastoma
  • phaeochromocytoma
38
Q

Tuberous sclerosis

A

“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
Q

Friedrich ataxia

A

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
Q

Huntington disease

A

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
Q

Duchenne muscular dystrophy

A

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
Q

Becker muscular dystrophy

A

Deletion/mutation is in frame

Therefore shottend semi-functional protein/milder phenotype

43
Q

Down’s

A

Trisomy 21 (95%)

  1. 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
Q

Fragile X

A

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
Q

Marfans

A

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

Genetics (5 decks)

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