15.1 Flashcards
Chromosomal abnormalities
- Numerical
- structural
Morphologic chromosomes classification
- Metacentric – centromere central
- Acrocentric – centromere terminal (satellites) -> centromere is on terminal end
- Submetacentric – centromere intermediate
Numerical Chromosome Abnormalities
- 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
Structural Chromosome Abnormalities
- 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
Structural chromosome abnormalities - unequal crossover
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
Chromosome abnormalities in more than one cell line
Mosaicism
- Two or more cells lines with different chromosomal make-up. Derived from one zygote. Non-disjunction during early embryotic mitotic division.
Name the common genetically determined diseases resulting from chromosomal numerical or structural abnormalities
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
Cytogenetics of Down syndromes
- 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
Clinical manifestations of Down syndrome
- 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)
Autosomal dominant inheritance
- 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
Familial Hypercholesterolemia
- 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)
Neurofibromatosis type 1
- 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)
Marfan Syndrome
- 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)
Achondroplasia
- 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
Autosomal recessive inheritance
- 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
Occulo-cutaneous albinism
- 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.
Sickle cell disease
- 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)
Cystic fibrosis
- 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
X-linked recessive inheritance
- 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)
Haemophilia
- x-linked recessive
- bleed around elbow
- retinal bleed
- deficiency of factor 8
- repeated, untreated joint bleed
Duchenne Muscular Dystrophy
- Dytrophinopathies
- Mutations in DMD gene
- Duchenne muscular dystrophy presents earlier with loss of ambulation between 7 – 13 year
- affectes males
- gower sign
- calf hypertrophy
Common genetic disease resulting from unusual mechanisms
- 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
Common genetically determined diseases resulting from polygenic or multifactorial inheritance
- 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
Teratogenic drugs
- Medication
- Drugs
- Alcohol
- Maternal illnesses (diabetes)
- Congenital infections
Teratogenic medications
- isotretinoin (roaccutane)
- wafarin
- anti-epileptic (valproic acid)
- ACE inhibitors
Other teratogens
- radiation
- diabetes (risk depends on control of diabetes)
- congenital infections (rubella)
Alcohol
- 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
