L8 - Chromosomal deletion and duplication syndromes Flashcards
describe deletion and duplication
alteration in chr seq not detectable by karyotype
arise aar of non allelic homologous recombination errors
considered copy no chnages
what more tolerated dup or del
dup
where are dup/del most likely to arise
where repeat seq are similar on the same chr or low copy no
low copy no with 97% seq id also predispose
how do del/dup occur in recomb
misalinment occurs at area where similar or low copy no
unequal crossingover
results in gain or loss of copy no
what are recurrent rearrangements
share breakpoints and common size
what are the nonrecurrent rearrangements
breakpoints scttered in the genomic region
are of uniwue size and genomic material in unrel inds
what is array comparative genomic hybridisation
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
are dup and del occur in equal number
in theory yes as production is reciprocal
but dup harder id
eg so far found 211 micro del syndromes vs 79 micro del`
what is the 11q22 micro dup syndrome gene compoents
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
what diseases is the MTOR complex already associated with (MTOR= LAMTOR” of 11q22 dup syndrome assoc with)
autism spectrum disorders
therefore making the LAMTOR2 good candiate for the pathological ptype seen
what is the charcot marie tooth syndrome
dup of pmp22
the reciprocal deletion - hereditary neuropathy wit liability to pressure palsies
what important about the discovery of charcot marie tooth syndrome
id by aCGH
confirm by qPCR
breakthrough
what the length of microdeletion syndrome deletion
vary 1kb-100skb
what eg of single gene del syndrome
alagille syndrome
What the genetic cause of alagille syndrome
JAG1 deletion - defect notch singalling
point mut in JAG1 confirm is the gene inv
JAG1 a mut dom gene - haploinsufficieny cause diseas
what patho ptype assoc with alagille syndrome
liver disease
heart disease
eye and skeletal defects
what is contiguous ene del syndrome and give eg
ptype due to loss of several linked genes common in x chr eg X linked agammaglobinemia - del of BTK and TIMM8A
what us segmental aneuploidy syndormes an eg of
special type of contiguous gene del syndrome with common occurence and recog ptype
give an eg of segmental aneuploidy syndormes
Digeorge and velocardiofacial syndrome
del of 22q.11.2
what special about digeorge syndorme
a 22q.11.2 deletion syndrome
have ptype but no known cause
22q.11.2 deletion syndrome how do they occur
aar of misparing of the lcr amd unequal crossing over in meiosis
what ptpe are assoc with 22q.11.2 deletion syndrome
cardiac defect - structural abn immune defect - lack thymus palate defect - musculare weakening dev delay psychologicla probs in later life
epidemology facts on 22q.11.2 deletion syndrome
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
what the gentic basis of 22q.11.2 deletion syndromes
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
what probems in study genetic of 22q.11.2 deletion syndrome
is patient variation in ptype = correlating genes and minor aspect of ptype difficult
what did mouse model show on the role of tbx1 in 22q.11.2 deletion syndrome
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
what common heart defect result from 22q.11.2 deletion syndrome
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
what gene link to digeorge and why
moz
a histtone acetyltransferase
ko results in tpye eg no thymus/cardia defect and celft palate/hypothyroid - similar to di george
what the molecular mechnaims behind the effect of moz mutants
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
what the ptype of 22q.11.2 dduplication
presence FISH rev
some healthy
some evidence of caridac defect
some other malform
