L8 - Chromosomal deletion and duplication syndromes

Question 1

describe deletion and duplication

Answer 1

alteration in chr seq not detectable by karyotype
arise aar of non allelic homologous recombination errors
considered copy no chnages

Question 2

what more tolerated dup or del

Answer 2

dup

Question 3

where are dup/del most likely to arise

Answer 3

where repeat seq are similar on the same chr or low copy no

low copy no with 97% seq id also predispose

Question 4

how do del/dup occur in recomb

Answer 4

misalinment occurs at area where similar or low copy no
unequal crossingover
results in gain or loss of copy no

Question 5

what are recurrent rearrangements

Answer 5

share breakpoints and common size

Question 6

what are the nonrecurrent rearrangements

Answer 6

breakpoints scttered in the genomic region

are of uniwue size and genomic material in unrel inds

Question 7

what is array comparative genomic hybridisation

Answer 7

seq genome on a chip 
mix with sample
allow to hybridise
green = more sample than control 
red = less sample than cotnrol 
can be used for exome and genoome

Question 8

are dup and del occur in equal number

Answer 8

in theory yes as production is reciprocal
but dup harder id
eg so far found 211 micro del syndromes vs 79 micro del`

Question 9

what is the 11q22 micro dup syndrome gene compoents

Answer 9

pathological cnv
dev delay and behav defects
11 known genes in region
inc LAMTOR2/LMNA/SEMA4A present as pr complex dup probs imbalances it and why ptype patholgical

Question 10

what diseases is the MTOR complex already associated with (MTOR= LAMTOR” of 11q22 dup syndrome assoc with)

Answer 10

autism spectrum disorders

therefore making the LAMTOR2 good candiate for the pathological ptype seen

Question 11

what is the charcot marie tooth syndrome

Answer 11

dup of pmp22

the reciprocal deletion - hereditary neuropathy wit liability to pressure palsies

Question 12

what important about the discovery of charcot marie tooth syndrome

Answer 12

id by aCGH
confirm by qPCR
breakthrough

Question 13

what the length of microdeletion syndrome deletion

Answer 13

vary 1kb-100skb

Question 14

what eg of single gene del syndrome

Answer 14

alagille syndrome

Question 15

What the genetic cause of alagille syndrome

Answer 15

JAG1 deletion - defect notch singalling
point mut in JAG1 confirm is the gene inv
JAG1 a mut dom gene - haploinsufficieny cause diseas

Question 16

what patho ptype assoc with alagille syndrome

Answer 16

liver disease
heart disease
eye and skeletal defects

Question 17

what is contiguous ene del syndrome and give eg

Answer 17

ptype due to loss of several linked genes 
common in x chr
eg 
X linked agammaglobinemia 
- del of BTK and TIMM8A

Question 18

what us segmental aneuploidy syndormes an eg of

Answer 18

special type of contiguous gene del syndrome with common occurence and recog ptype

Question 19

give an eg of segmental aneuploidy syndormes

Answer 19

Digeorge and velocardiofacial syndrome

del of 22q.11.2

Question 20

what special about digeorge syndorme

Answer 20

a 22q.11.2 deletion syndrome

have ptype but no known cause

Question 21

22q.11.2 deletion syndrome how do they occur

Answer 21

aar of misparing of the lcr amd unequal crossing over in meiosis

Question 22

what ptpe are assoc with 22q.11.2 deletion syndrome

Answer 22

cardiac defect - structural abn
immune defect - lack thymus
palate defect - musculare weakening 
dev delay 
psychologicla probs in later life

Question 23

epidemology facts on 22q.11.2 deletion syndrome

Answer 23

no gender diff
no founder effect
FISH first use but probs under detected new techs reveal higher freq of atypical in the region than prev thought

Question 24

what the gentic basis of 22q.11.2 deletion syndromes

Answer 24

haploinsufficiency of tbx1
causes sim ptype
tbx1 mut in pateint with the ptype but no del = confirms is this gene major inv
no ther gens attributed to ptype seen

Question 25

what probems in study genetic of 22q.11.2 deletion syndrome

Answer 25

is patient variation in ptype = correlating genes and minor aspect of ptype difficult

Question 26

what did mouse model show on the role of tbx1 in 22q.11.2 deletion syndrome

Answer 26

tbx1 norm expr in secondary heart field
which then develops into outflow tract
= area norm effected in the syndrome
tb1 norm act fgf8 to promote prolif and represses srf which control cell diff

Question 27

what common heart defect result from 22q.11.2 deletion syndrome

Answer 27

trunucus arterious - aar of decr prolif of outflow tract
= failure of of to divide into aorta and
pulmonary vessels
interupted aortic arch - aar of lack of tbx1 in 2 heart field
no ncc prolif which norm
contrib to the arch formation
tetraology of fallot - complex heart malformations / dev cause unkown but defective dev of rhs of heart

Question 28

what gene link to digeorge and why

Answer 28

moz
a histtone acetyltransferase
ko results in tpye eg no thymus/cardia defect and celft palate/hypothyroid - similar to di george

Question 29

what the molecular mechnaims behind the effect of moz mutants

Answer 29

mox imp in histone modification
in a moz mut there is less h3k9ac on tbx1 promoter (assoc with act)
and incr in h3k9me3 (assoc with repr) on teh tbx1 promoter
= so important for tbx1 act

Question 30

what the ptype of 22q.11.2 dduplication

Answer 30

presence FISH rev
some healthy
some evidence of caridac defect
some other malform