Whole genome analysis 1 (changed 28/2 & 25/3)
Analysis of chromosomal disorders in the clinic
Aims
Describe common chromosomal abnormalities and how they arise understand the breath of indications for chromosomal analysis understand the diagnostic techniques used to analyse chromosomal structure be familiar with the interpretations of a karyotype describe the features of the des chromosomes and the clinical consywuances of numerical abnormalities describe features and causes of the common aneuploidies describe the origin an doutcomes of balanced recuprocal and robertsonian translocation and toher strucural alterations.
What is a chromosome
one strand of DNA Which contain a large amount of information and is innately important
Chromosome structure and nomenclature.
Cells grown and giemsa staining dark bands inactive light bands active chromosomes ordered by side and centromere positon acrocentric, and metacentric the short aems of acrocentric chromosomes house repetitive duplicated DNA the bands are numbered from centromere to telomere long arm queue short arm petite
Karyotype nomenclature
• 1-22: autosome numbers • X,Y: sex chromosomes • /: mosaicism eg. 46/47 • p: short arm • q: long arm • del: deletion • der: derivative (rearranged) chromosome • dup: duplication • i: isochromosome • ins: insertion • inv: inversion • r: ring chromosome • t: translocation • ter: terminal pter, qter
46,XY,t(5;10(p13;q25) t denotes translocation between chromosome 5 and 10 from p(short arm) at band 13 from chromesome 5 and q (long arm) at band 25 in chromosome 10
47,XY,+21 46 chromesomes x and y so male extra chromesome 21
46,XX,+13, der(13;21)(q10;q10) 46 chromosomes but extra 13 this means extra 13 has been grafted into 21
46,XX,dup(2)(p13p22)
The essence of chromosomal basis of disease states is balance
- 50% of spontaneous abortion
- 10% of still born
- 0.7% of liveborn have chromosomeal abnormalities
X inactivation inactivated about 80% of each X chromosome (lionisation?)
Chromosomal microarray
At high resolution there are many many duplications and unbalancements
3400 children many deletions and duplications
The challange is distinguishing what is pathological from normal
Clinical indications for assessing chromosomal abnormalities
- Abnormality of growth or development
- Intellectual disability
- Recurrent miscarriage
- Investigation of cancers
Abnormality of growth or development
Turner syndrome
present with:
- coarctation of aorta
- linear growth delay
- primary amenorrhoea
- neonatal oedema/webbed neck
Causes
75% have a 45,X0 25% have a structural abnormality of one X chromosome (like deletion or a ring chromosome)
How does it occur?
Postzygotic change, after conception
After conception XY → X0 XX → X0
Klinefelter syndrome
Presents as: reduced testicular function tall stature and left shifted IQ
Causes:
XXY (second X undergoes X inactivation) meiotic nondisjunction
Intellectual disability
Down syndrome
karyotype fluorescent dye for ch 21 chromesomal sequencing whole genome sequencing (not often used)
Causes
96% free standing 3-4% robertsonian translocation 1-2% postzygotic
Current screening programme in place
new technology enables sequencing of placental DNA from maternal blood stream