Unusual Patterns of Inheritance Flashcards
What is the inheritance pattern of complex traits?
Polygenic - influenced by many genes which often interact with environmental factors = multifactorial inheritance
What are the confounding factors in monogenic inheritance?
- Variable expression - same mutation expressed as different disease phenotypes
- Reduced penetrance - not everyone with genetic factors shows symptoms
- Sex limitation - mutation predisposes to disease/phenotype in one sex rather than other
- Phenocopy - occurrence of disease in family unrelated to familial mutation
What are the 2 major dominant susceptibility genes for hereditary breast cancer?
- BRCA1
- BRCA2
Give an example of X-linked dominant inheritance
X-linked hypophosphatemic rickets
Give an example of X-linked dominant lethal disease
- Incontinentia pigmenti (NEMO gene)
- Affects women - so severe for men they are non-viable
What is seen in affected females with incontinentia pigmenti?
- Blistering (birth - 4m)
- Wart-like rash (several months)
- Swirling macular hyper-pigmentation (6m - adult)
- Linear hypo pigmentation
- Alopecia, hypodontia, dystrophic nails, retinal detachment, occasional developmental delay
Why does incontinentia pigmenti affect females?
- In females, 1 X-chromosome silenced in each cell
- Inactivation takes place randomly around blastocyst stage
- Daughter cells from embryonic cell inherit same inactivated X-chromosome
Either:
1. Normal X-chromosome inactivates = cells with NEMO
2. Mutated X-chromosome inactivated = normal X passed on
What is the recurrence risk of incontinentia pigmenti?
1/3 unaffected male
1/3 affected female
1/3 unaffected female
Affected males die in utero
What is chimerism?
An organism composed of 2 or more populations of genetically distinct cells that originate from different zygotes.
What is a constitutional mutation?
Inherited from a gamete (gremlin mutation) or occurs soon after fertilisation = present in every cell
What is somatic mosaicism?
Some cells lack mutation = milder phenotype.
However, their children = at risk of inheriting change as constitutional mutation = more severe phenotype.
What is confined placental mosaicism?
Common + can complicate prenatal testing but is absent from baby
What is the cause and presentation of Prader Willi Syndrome?
Cause = deletion inherited on PATERNAL chromosome 15
- Neonatal hypotonia + early poor feeding
- Later = hyperrhagia + obesity
- Short stature, hypogonadism
- Mild/mod ID, behaviour problems
What is the cause and presentation of Angleman Syndrome?
Cause = deletion inherited on MATERNAL chromosome 15
- Microcephaly, gait ataxia, seizures
- Severe ID, absent speech, happy demeanour
What is genomic imprinting?
- When genes expression is dependant on which parent it was inherited from
- Involves epigenetic signals
Define epigenetics
- Modification on chromosomes without alteration of DNA sequence
- Alter transcriptional potential of genes through DNA methylation or histone modification
Give an example of imprinted inheritance
Mother with PWS could have child with AS:
If they inherit deletion paternally but they are mother so reprogram + maternally imprint + pass on
What is Uniparental disomy (UPD)?
- When BOTH chromosomes originate from 1 parent
- Due to non-disjunction at meiosis 1
- Can have UPD of chromosome + be healthy as long as NO imprinted genes on chromosome
What is trisomic rescue?
Loss of chromosome from zygote/early embryo -> preserves viability
What are potential health problems associated with UPD?
- Mosaic aneuploidy (if trisomy/monosomy rescue)
- Disease due to imprinting
- Recessive disease (if isodisomy)
What is the presentation of Beckwith-Wiedemann syndrome?
- Large gestational age
- Exomphalos/umbilical hernia
- Macroglossia
- Limb/body overgrowth
- Neonatal hyper-insulinism
- Ear creases
- Nevus flames
- Risk of cancer
What is the presentation of Silver-Russel syndrome?
- Small for gestational age
- Feeding problems
- Hypoglycaemia
- Lack of subcutaneous fat
- Clinodactyly
- Proportionate short stature
- Asymmetry
- Hypospadias
- Normal intelligence
What is mitochondrial inheritance?
- Transmission from mother to child
- Sperm do not transmit paternal mitochondria
- Only maternal mitochondria present in cytoplasm of zygote
Which tissues are particularly vulnerable in mitochondrial disorders?
- Energy-hungry tissues
- Often multi-system
What is Leber Hereditary Optic Neuropathy (LHON)?
- Sudden, painless, permanent central vision loss, bilateral
- Optic atrophy
- Onset in adolescence or as young adult, but can be earlier/later
- 3 mtDNA mutations cause 95% of LHON
- Male predominance, but with reduced penetrance in both sexes
Do all mitochondrial disorders have mitochondrial inheritance?
- No, only some mitochondrial disorders have mitochondrial inheritance
- Many proteins in mitochondria come from genes encoded in nuclear genome
- Disorders of mitochondrial function can be inherited in autosomal or X-linked manner
What is Heteroplasmy?
Where proportion of mutated mitochondria in cell varies between tissues -> affecting which organs have symptoms = variable expression
What is Y-linked inheritance?
- Few traits as not many genes
- Often involved in fertility - mutations impair reproduction
- Male-male transmission only
What is Pseudo-dominant inheritance?
When recessive conditions appear to transmmit dominantly
What is Co-dominant inheritance?
e. g. ABO blood group
- A + B alleles both co-dominant
- O allele recessive to both
What is anticipation?
- Symptoms of genetic disorder become more severe and/or have earlier onset in successive generations
- Characteristic of trinucleotide repeat disorders
- Can be coding or non-coding
What is the difference between Heterodisomy and Isodisomy?
- Heterodisomy = no-disjunction at meiosis stage 1
- Isodisomy = non-disjunction at meiosis stage 2
