15.1 Flashcards

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1
Q

Chromosomal abnormalities

A
  • Numerical
  • structural
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2
Q

Morphologic chromosomes classification

A
  • Metacentric – centromere central
  • Acrocentric – centromere terminal (satellites) -> centromere is on terminal end
  • Submetacentric – centromere intermediate
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3
Q

Numerical Chromosome Abnormalities

A
  • Monosomy – absence of one chromosome (Turner syndrome)
  • Trisomy – one extra chromosome (Trisomy 21, Trisomy 13, Trisomy 18)
  • Tetrasomy – two extra chromosomes
  • Polyploidy - Addition complete sets of chromosome
    ➡️Triploidy – one additional set
    ➡️Tetraploidy – two additional complete sets
  • Isochromosome
    ➡️one arm duplicated (and the other lost) due to transverse separation of centromere
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4
Q

Structural Chromosome Abnormalities

A
  • Deletion - Loss of a section of a chromosome
  • Microdeletion - Loss of a section of a chromosome (<5MB)
  • Duplication - Gain of a section of a chromosome
  • Insertions - part of a chromosome repositioned into same or different chromosomes
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5
Q

Structural chromosome abnormalities - unequal crossover

A

Ring chromosome
- Two breaks, one on the short arm and one on the long arm in which broken ends are attached forming a circular configuration.

Inversions
- Segment of a chromosome is reversed in orientation

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6
Q

Chromosome abnormalities in more than one cell line

A

Mosaicism
- Two or more cells lines with different chromosomal make-up. Derived from one zygote. Non-disjunction during early embryotic mitotic division.

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7
Q

Name the common genetically determined diseases resulting from chromosomal numerical or structural abnormalities

A

Numerical chromosome abnormalities - autosomes
- Down syndrome
- Trisomy 13
- Trisomy 18

Numerical abnormalities of the sex chromosomes
- Turner syndrome
- Klinefelter syndrome (47, XXY)
- 47, XXX, 47, XYY

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8
Q

Cytogenetics of Down syndromes

A
  • Majority result from non-disjunction giving rise to trisomy 21 (extra chromosome)
  • Robertsonian translocation (14;21 translocation) – familial
  • Mosaicism (post-zygotic non-disjunction) -> rare
  • To determine the mechanism – karyotype analysis is needed
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9
Q

Clinical manifestations of Down syndrome

A
  • Delayed milestones
  • Intellectual disability (mild)
  • Cardiac defects (atrial, ventricular & septal defects, Antroseptal ventricular defect is most common)
  • Medical complications (hypothyroidism and increased incidence of ALL) -> increased risk for leukaemia
  • Adulthood - dementia at earlier age

Neonatal manifestations
- Irregular muscle tone
- classic dimorphic features (flat ears, flat face, brachycephaly, protruding tongue)
- saddle gap (gap between toes)
- abnormal palmar creases (because of shortening of carpals -> brachy-actilly)

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10
Q

Autosomal dominant inheritance

A
  • infected individual in each generation
  • male and female equally effected
  • affected individuals in multiple generations
  • one mutant copy needed for expression
    Many disorders
  • Familial hypercholesterolaemia
  • Neurofibromatosis
  • Marfan’s syndrome
  • Achondroplasia
    Variable expressivity.
  • clinical features can show striking variation from person to person, even in the same family.
    Reduced penetrance
  • An individual who has no features of a disorder despite being heterozygous for a particular gene mutation

Non-penetrance
- carrier

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11
Q

Familial Hypercholesterolemia

A
  • Autosomal dominant
  • High levels of LDL
  • Mutations in the LDLR gene (>700 mutations)
  • Causes premature coronary artery disease
  • Heterozygous/homozygous forms
  • Founder effect- Afrikaner population
    (1 in 100 individuals affected)
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12
Q

Neurofibromatosis type 1

A
  • autosomal dominant

Clinical features:
- Café-au-lait patches
- Plexiform neurofibromas
- Lisch nodules
- Axillary and inguinal freckling
- Dermal neurofibromas

  • Age-dependent expression,
  • Variable expression
  • 100% penetrant (if you have mutation, you will have condition)
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13
Q

Marfan Syndrome

A
  • autisomal dominant
  • Connective tissue disorder
  • Complications: Aortic root dilatation and ectopia lentis are important complications

Clinical features:
- Limb abnormalities
- upper to lower segmenent is reduced
- charateristic face features
- chest wall abnormalities (pectus excavatum)

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14
Q

Achondroplasia

A
  • common skeletal dysplasia
  • inherited from affected parent or de novo mutation
  • May be inherited from an affected parent in an autosomal dominant manner
  • May occur de novo
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15
Q

Autosomal recessive inheritance

A
  • Two copies needed for expression
  • Both parents are carriers, generally clinically normal
  • Family history may be negative or prior children affected
  • Affected individual usually in a single generation
  • Horizontal pattern
  • Equal number of affected males and females
  • Consanguinity may be present / rare recessives
  • Little clinical variability

Many disorders
- Metabolic disorders (galactosaemia)
- Cystic Fibrosis
- Sickle cell anaemia
- Rare disorders

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16
Q

Occulo-cutaneous albinism

A
  • Common throughout sub-Saharan Africa (carrier frequency)
  • Increased risk for skin cancer
  • Visual impairment
  • Lack of pigment due to mutations in melanin synthesis and transport pathway.
17
Q

Sickle cell disease

A
  • Autosomal recessive
  • Condition that affects shape of haemoglobin molecules, O₂ carrier in blood.
  • Common in North Africa, India, Mediterranean, Middle East.
  • Moderate to severe anaemia
  • Jaundice
  • Acute sickle events/crises (pain, haemolysis, acute chest syndrome, neurological complications)
  • p.Glu6Val in HBB (homozygotes)
18
Q

Cystic fibrosis

A
  • autosomal recessive
  • CFTR gene
  • Many mutations are described
  • Most common p.phe508del
  • Genetics becoming important for therapies in the future
  • Affects many systems- pulmonary disease, pancreas insufficiency, male infertility
19
Q

X-linked recessive inheritance

A
  • Usually only males are affected (hemizygous)
  • Females (heterozygotes are unaffected)
  • Unaffected females transmit to males
  • No male to male transmission
  • Family history has more affected males
  • Carrier females may show milder symptoms/manifesting

Diseases
- Haemophilia A
- Dystrophinopathies (Duchenne and Becker muscular dystrophy)

20
Q

Haemophilia

A
  • x-linked recessive
  • bleed around elbow
  • retinal bleed
  • deficiency of factor 8
  • repeated, untreated joint bleed
21
Q

Duchenne Muscular Dystrophy

A
  • Dytrophinopathies
  • Mutations in DMD gene
  • Duchenne muscular dystrophy presents earlier with loss of ambulation between 7 – 13 year
  • affectes males
  • gower sign
  • calf hypertrophy
22
Q

Common genetic disease resulting from unusual mechanisms

A
  • Some genetic conditions are caused by unusual mechanisms:
  • conditions where mutations is due to repeat expansions

Triplet repeat disorders
➡️Huntington’s disease
➡️Spinocerebellar ataxias
➡️Mytonic dystrophy

Epigenetic disorders
- prader-willi syndrome
- beckwith wiedeman syndrome

23
Q

Common genetically determined diseases resulting from polygenic or multifactorial inheritance

A
  • Some genetic disorders are caused by either a chromosome abnormality, singe gene, epigentic disorder
  • Some disorders are multifactorial, many genetic factors (polygenic, low penetrance genes) and environmental factors may play a role
  • non-syndrome tube defects
  • cleft lip palet
  • autism
24
Q

Teratogenic drugs

A
  • Medication
  • Drugs
  • Alcohol
  • Maternal illnesses (diabetes)
  • Congenital infections
25
Q

Teratogenic medications

A
  • isotretinoin (roaccutane)
  • wafarin
  • anti-epileptic (valproic acid)
  • ACE inhibitors
26
Q

Other teratogens

A
  • radiation
  • diabetes (risk depends on control of diabetes)
  • congenital infections (rubella)
27
Q

Alcohol

A
  • Alcohol is the commonest teratogen in South Africa, and worldwide

DEFINITIONS:
FASD (fetal alcohol spectrum disorder):
- A continuum of disabilities related to effects on developing brain
- Alcohol related neurodevelopmental disorder (ARND),alcohol related birth defect (ARBD)

FAS (fetal alcohol syndrome):
- Most severe end of the FASD spectrum
- Has a characteristic pattern of dysmorphic features

Basic principals
- Alcohol easily crosses the placenta
- Exact molecular mechanism causing FAS unclear (but alcohol affects GABA receptors in the brain)
- Susceptibility varies by stage of fetal development
- Dosage plays a role
- People vary in susceptibility
- seceptability varies on stage of fetal development
- brain throughout pregnancy

Susceptibility maternal risk factors
Slide 38
- thin, small stature (⬆️BAC per drink)
- unplanned pregnancy
- unaware of FAS risk
- smoker
- poor nutrition
- depressed
- partner & friends drink
- genetics

Clinical manifestations
- Microcephaly
- Growth restriction
- Dysmorphic features (short palpebral fissures), smooth philtrum and thin vermillion border
- Limbs – radiolunar synostosis, clinodactyly
- Cardiac defects (birth defects)
- Behavioural/cognitive/learning difficulties