What is the most common cause of trisomy?
Nondisjunction at Meiosis 1
In what two situations would a karyotype detect a problem that microarray wouldn’t?
Balanced translocation
AND
Inversion
What situations would be detected by microarray but NOT by karyotype?
Micro-deletion
Micro-duplication
Micro-unbalanced translocation
What is the Hardy Weinberg principle for assessing risk of carrier status for a recessive condition?
p^2 + 2pq + q^2 = 1
where p = normal (ie AA)
q = homozygous recessive allele (aa)
2pq = carrier (Aa)
How would you calculate the carrier frequency using Hardy Weinberg if you are given a population frequency?
Population frequency of a condition is 1 in x
q = square root of 1/X
Carrier frequency = 2q (you assume p=1 given q is so small)
ie 1 in 6,400
Square root of (1/6,400)
=0.0125
carrier frequency = 2x = 0.025
(divide 1 by answer to get 1 in x format)
1 in 40
What is the main mechanism behind autosomal dominant inherited conditions?
Haploinsufficiency
Less common
- dominant negative
- gain of function
What is the risk of offspring acquiring autosomal dominant condition?
1 in 2 (50%) as only requires one allele of the gene pair
What are the key features/clues to autosomal dominant transmission?
Gender independent (M and F affected)
Male to male transmission
Vertical transmission - affects multiple generations
Penetrance = all or nothing
Expressivity = degree of effect/severity of manifestations
What are some common autosomal dominant conditions?
Neurofibromatosis
Tuberous sclerosis
Myotonic dystrophy
Huntington disease
Familial hypercholesterolaemia
Marfans
Most Ehlers Danlos
Achondroplasia
Osteogenesis Imperfecta
Adult polycystic kidney disease
Various inherited cancer syndromes incl
BRCA1 and 2
MEN
Lynch syndrome
Von Hippel Lindau
Genetic syndromes
Noonan syndrome
Williams syndrome
What are some complicating factors in Autosomal Dominant inheritance?
Anticipation = tendency in a genetic condition for successive generations to present at an earlier age and/or with more severe manifestations
Mosaicism = genetically different cell lines within an individual. may be at single gene or chromosomal level, is a post-fertilisation event
Imprinting = differential gene expression depending on parent of origin
Which conditions do we more commonly see mosaicism?
Chromosomal
- Turner syndrome
Single gene
- NF1 (somatic)
- tuberous sclerosis (somatic)
- DMD (gonadal)
- achondroplasia (gonadal)
What is the difference between mosaicism and chimerism?
Mosaic individual has 2 or more genetically different cell lines derived from the same zygote
whereas
Chimeric individual has two or more genetically different cell lines derived from two or more zygotes
What are the key features of X-linked inheritance?
No male to male transmission
Vertical transmission present
Sex dependent
- if recessive - excess males affected, if females affected tends to be milder eg DMD
- if dominant - males tend to be prenatally lethal; females affected eg incontinenti pigmenti
What is X-linked inactivation?
Occurs when one of the two X chromosomes (maternal or paternal) is randomly inactivated in early embryogenesis
What are the key features of mitochondrial inheritance?
Actually most mitochondrial genes are encoded in the nucleus -> mendelian inheritance (eg autosomal recessive, X-linked)
For true mitochondrial inheritance - get random assortment meaning each daughter cell may receive different proportions of mitochondria carrying normal vs mutant mtDNA
Extremely variable phenotypic expression due to heteroplasmy and threshold
In general, only egg cells contribute mitochondria to offspring thus mitochondrial mutations exhibit matrilineal inheritance
What is heteroplasmy?
the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual
What does threshold refer to in mitochondrial disorders?
The number of mutant mtDNA beyond which get phenotypic expression (clinical manifestations)
What is Lyonisation?
Lyonization (also called X-inactivation) refers to the normal phenomenon in which one of the two X chromosomes in every cell of a female individual is inactivated during embryonic development. This inactivation prevents females from having twice as many X chromosome gene products as males, who possess only a single copy of the X chromosome.
What is matrilineal inheritance?
Children inherit maternal mtDNA from mother
so all maternal offspring are at risk of mtDNA disorders (equal chance male and female offspring)
No transmission from male to his offspring
Proportion of offspring affected is variable/random
When do imprinted genes cause disease?
Imprinted genes cause disease with the maternal or paternal gene that is usually expressed is silenced
What does uniparental disomy refer to?
When both chromosomal regions are inherited from the same parent
What are some examples of conditions with imprinting?
Prader-Willi syndrome
Angelman syndrome
Albright hereditary osteodystrophy
What are the key features of Prader-Willi syndrome?
99% of cases have abnormal methylation
- paternally inherited genes active
- maternal methylated/silenced
Causes
Polyhydramnios
Hypotonia
Feeding problems
Short stature
Obesity
Developmental delay/intellectual disability
Small hands and feet
Hypogonadotropic hypogonadism
What is the effect of loss of imprinting on an affected gene?
Activation of the normally silenced gene
