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Origins of inherited and sporadic mutations (Gender specific differences…
Origins of inherited and sporadic mutations
Human aneuploidy
Leading cause of congenital birth defects and miscarriage
Majority from maternal nondisjuntional errors
Many aneuploidies demonstrate a maternal age effect
Estimated incidence of human aneuploidy
Spontaneous abortions = >35%
Preimplantation embryos = 20-40%
Eggs = 10-35%
Sperm = 1-4%
Gender specific differences in meisosis (MAT mainly)
Differences in the way it works between males and females
Key to understand age effect and maternal bias
Female follicles undergo dictiate arrest for much longer than males and have the same protein cohesin complex throughout this time
Recombination
Failure to recombine has been demonstrated to cause human trisomy
Females have at least one crossover-less bivalent in over 10% oocytes
Types of recombination
Achiasmate
Trisomy 18 and 21
Distal
Trisomy 16 and T21
Proximal
T21
Loss of sister chromatid cohesion
The cohesion complex pulls together the bivalents and is established in pre-meiosis S-phase
Cohesion complex is not replenished or renewed so degradation can be expected over time
This can cause loss of sister chromatid cohesion
Longer cells in the dictiate arrest = more degredation
Spindle Assembly Checkpoint
Lack of association results in univalents
In female mice, the presence of single univalent does not delay entry into anaphase (males it does)
PATERNAL
Paternal age effect disorders
Often associated with Rasopathies
Mutations in the RAS pathway
Apert, Crouzon, Pfeiffer, achondroplasia, Noonan, multiple endocrine neoplasia types 2A and 2B
Achondroplasia
Mutations in FGFR3 (95%) = p.Gly380Arg)
Can be seen on US 20w<
Short femur length, frontal bossing, trident hands
Mechanism of 'selfish' selection - sperm with these mutations are positively selected for and this leads to progressive clonal expansion
Similar mutations found in testicular neoplasms in older men
Ras pathway linked to growth and cell proliferation
Mosaicism
An individual developed from a single fertilised egg that has two or more populations of cells with distinct genotypes
Often a milder phenotype
Can be difficult to interpret
May expect mosaicism of other chromosomes
Different outcome options
If cell division error occurs early on, mosaicism more likely to be generalised
If cell division error occurs at a later stage, mosaicism may be confined to the embryo or placenta
May be more specific still in the embryo and be confined to specific organs
Confined placental mosaicism
May have only arose in placental cells
May be a result of aneuploidy rescue
Loss of chromosome if trisomy; gain of chromosome if monosomy
Can result in CPM
Can result in UPM
May have consequences of recessive disease or imprinted region
Microdeletions and duplications
Mechanism
Can be recurrent or non-recurrent
Segmental duplication regions of highly repetitive regions can result in susceptibility
NAHR (non-allelic homologous recombination)
NHEJ (Non-homologous end joining)
FoSTeS (fork stalling and template switching)
22q11.2
DiGeorge and VCF syndromes
~3Mb hemizygous deletion of 22q11
Recurrent
Caused by NAHR
Phenotype:
Facial dysmorphia
Cardiac defects
Thymic hypoplasia
Velopharyngeal insufficiency
Parathyroid dysfunction
Reduced IQ
Prenatally possibly detectable: CHD or renal anomaly
Enhanced maternal origin
Williams-Beuren Syndrome
Phenotype:
Dysmorphic face
CV abnormalities
Hoarse voice
Abnormal gait
Short stature
Low IQ
1.5-1.8Mb microdeletion on 7q11.23
Common inversion polymorphism and these people are more likely to get a deletion in this region
7q11.23 Dup Syndrome
Phenotype:
Distinctive facial features
CV disease
Neurological abnormalities
Childhood apraxia of speech
Selective mutism
ADHD/ASD
Delayed motor, speech and social skills