Cytogenetic imbalance (Gains) Flashcards
What forms of cytogenetic gains are there?
Gain of material is better tolerated than loss
- Primary trisomy (meiotic non-dysjunction or mitotic with mosaicism)
- Segmental duplication (interstitial duplication, insertion, marker chromosomes)
- Unbalanced form of reciprocal translocation
Name the viable primary autosomal trisomies
Non-mosaic:
21- Down syndrome
13- Patau syndrome
18- Edward syndrome
Mosaic:
trisomy 8 and 9
Causes of Down syndrome
94% trisomy 21 with majority due to maternal non-dysjunction in meiosis I
4% unbalanced Robertsonian translocation (majority de novo, can be inherited from balanced carrier parent)
2% mosaic (post-zygotic mitotic non-dysjunction or tricomy rescue)
Clinical features of Down syndrome
flat facial profile upslanting palpebral fissures small ears brachycephaly protruding tongue bilateral single palmar crease short poor muscle tone mild to moderate ID Autistic spectrum disorder Cardiac defetcs Increased risk of Leukaemia (particularly in childhood)- can be transient not requiring treatment
Patau syndrome
Causes:
Trisomy 13
Unbalanced Robertsonian translocation
Clinical features: Severe ID microcephaly polydactyly (usually post axial) Holoprosencephaly Cleft palate nose and eye abnormalities Reduced life expectancy (80% die within 1 year)
Edward syndrome
Causes:
Trisomy 18 (95%)
Trisomy 18q- 46,XX,i(18)(q10)
Clinical features: Microcephaly Prominent occiput Micrognathia Hypertelorism Clenched hands Rockerbottom feet Heart defects Omphalocoele Severe ID Severely reduced life expectancy kidney malformation arthrogryposis cleft lip/palate
Mosaic trisomy 8
Mild to moderate ID Prominent forehead Campodactyly Deep palmar and plantar furrows urinary and cardiac abnormalities common
Cause by non-dysjunction during mitosis
isochromosome 8p has same phenotype
Mosaic trisomy 9
Low birth weight Developmental delay ID Congenital heart disease Strctural anomalies of the brain
What is a duplication and how do they originate?
An additional copy of a segment of a chromosome is present
Can originate by unequal crossing over during meiosis (reciprocal product deletion), or from meiotic events in the parent with a translocation, inversion, or isochromsome
Partial trisomy usually less of an effect on phenotype than monosomy
What is the difference between a direct and inverted tandem duplication?
The duplication comprises chromatin from the same chromosome.
Direct duplication: the orientation of the duplicated segment is maintained
Inverted duplication: the orientation is reversed
Inverted duplications may exist together with a terminal deletion arising from NHEJ or NAHR occurring in a pre-meiotic mitosis e.g. inv del/dup 8p
How does additional material from a different chromosome arise?
Can arise due to pairing between non-homologous chromosomes (NAHR or NHEJ) followed by a crossover
If a single segment is exchanged, a duplication or deletion is caused
If this occurs during meiosis it can result in unbalanced gametes depending on segregation
ESAC
Extra structurally abnormal chromosomes
What is a supernumerary marker chromosome?
An additional chromosome of unknown chromosomal origin
Most are small and often mosaic
Clinical significance depends of genetic composition
C-banding, DA-DAPI and silver staining of chromosomes were traditionally used to establish whether heterochromatin/euchromatin
Parental studies may also help determine clinical significance
May result in partial trisomy/tetrasomy
Pallister Killian Syndrome cytogenetic abnormality
Mosaicism for additional isochromosome consisting of 2 copies of i(12p) (tetrasomy 12p)
Tissue specific expression common. rarely observed in blood lymphocytes at metaphase (maybe observed in interphase or in fibroblasts)
De novo, caused by meiotic non-dysjunction and trisomy rescue in early mitotic diviisons
Pallister Killian syndrome clinical features
Developmental disorder affecting many parts of the body
Hypotonia in infancy (difficulty feeding) ID causing developmental delay Limited or absent speech hypo and hyperpigmented patches of skin Distinctive coarse facial features: -high forehead -sparse hair -hypertelorism and epicanthal folds -short nose -widely spaced eyes
May include: hearing loss vision impairment seizures genital abnormalities heart defects
