Presentation Magnus Nordenskjöld (, 5 Mb)
Transcript of Presentation Magnus Nordenskjöld (, 5 Mb)
-
Clinical Genetics / Klinisk Genetik
Magnus NordenskjldProfessor/ consultant
Department of Molecular Medicine & Surgery
-
?
-
100%Environment
100%Genetic
Hit b
y ligh
tning
Tube
rculo
sis
Mea
sles
Body
wei
ght
Spina
bifid
a
Canc
er
Diab
etes
Stat
ure
Sex
Cystic fibrosisDown syndrome
Blood group
Coro
nary
hea
rt dis
eas
e
Appe
ndici
tis
-
!"#
$#%
&
-
()*
1900"+
1902,*% ,-.)
-
1953/#01
23-
-
1956/3(41,5+###
1959/54)#)(#
-
2001 % (3)#$,6)
-
"7$7*8$997:8:Victor McKusick, Mendelian Inheritance in Man, OMIM
1966 1986 2011
AUTOSOMALT DOMINANT 837 2201 3807
AUTOSOMALT RECESSIVE 531 1420 3788
X-LINKED RECESSIVE 119 286 660____ ____ ____1487 3907 8255
3,275 diseases with known molecular basis (DNA)
-
Human haploidgenome
Important size correlation in genetics
Exon
Gene
mRNA
Chromosome bandChromosomes
1 bp9
3x 10 106
109
103
Resolution of genetic methodsPCR
Southern-blotFISH
Gene probes Painting
Chromosome analysis
DNA-sequensing
Disease causing mutations
Achondroplasia
Down Syndrom Trisomy 13
Cri du Chat5 p -
Myotonicdystrophy
Huntington chorea 22q11-
syndrome
Williams syndrom
1 bp9
3x 10 106
109
103
MLPAGene dose- array
-
Genetic disordersGenetic disorders
Chromosomalaberrations
Multifactoriel(complex) disorders
Monogenicdisorders
-
Causes of Mental retardation
Monogenic etc
Chromosome aberrations
Microdel/microdup
Multi-factorial
Environmentalfactors
Unknown
-
Edvin Boy born in 1993 Low birth weight, op due to ASD (atrial septal defect) and VSD (ventricular
septal defect) Delayed development , mental retardation Obese , elongated face , narrow chin, crowding teeth , high palate . Can not read, only a few spoken words
1998- Chromosome analysis
2005- Prader Willi analysis Fragilt-X analysis Sub-telomere screening
-
Edvin
2008-
Array-CGH
Diagnosis:8p23.1 deletion syndrome
Del(8)(p23.1p23.1), 3,8Mb
-
Array-CGH
-
Array-CGHPatient DNA Reference DNA
-
Copy number variants (CNV)
Alternative technology:
SNP- array
Single nucleotide polymorphisms
Array CGH
Comparative genomic hybridization
-
Array-CGH
-
Jacob
Boy born in 2007 (10 months at referral) Clearly retarded psycho-motor development Presents with nystagmus at a few months of age. Signs of delayed
myelinisation Can not move change place Limited communication
-
Jacob 2008-
Array-CGH
Diagnosis:Pelizaeus-Merzbacherdisease
Neurodegenerative disorder X-linked recessive Unaffected mothers can be gene carriers (2/3) 1/100 000 ( 10 cases in Sweden)
Dup(X)(q22.1q22.1), 800kbPLP1-gene
-
Jacob
??
?
PGD
-
Genetisk diagnostik
; &
IVF Embryo biopsy Genetic diagnosis
Pre-implantatoric Genetic DiagnosisPGD
-
Embryo biopsy
-
Causes of Mental retardation
Monogenic etc
Chromosome aberrations
Microdel/microdup
Multi-factorial
Environmentalfactors
Unknown
Probably many different single gene mutations
-
Human haploidgenome
Important size correlation in genetics
Exon
Gene
mRNA
Chromosome bandChromosomes
1 bp9
3x 10 106
109
103
Resolution of genetic methodsPCR
Southern-blotFISH
Gene probes Painting
Chromosome analysis
DNA-sequensing
Disease causing mutations
Achondroplasia
Down Syndrom Trisomy 13
Cri du Chat5 p -
Myotonicdystrophy
Huntington chorea 22q11-
syndrome
Williams syndrom
1 bp9
3x 10 106
109
103
MLPAGene dose- array
-
Future genetic research and diagnostics
Diagnostic toolbox
Specificity and accuracy Most types of disease-causing mutations can be identified
Limited throughputWe need to screen many disease genes in a patient
FutureNGS Next Generation Sequencing/ MPS Massive Parallel Sequencing
Sequence all genes / entire genome of one individual
-
Thank you !
-
Figur 3
-
Figur 3
-
Figur 3
-
1859
-
1865*!")
-
MONOGENIC DISEASES Levels of knowledge
Clinical description & mode of inheritance (Mendel)
Specific defect known Localization to a chromosomal region DNA RNA protein Mapping
The genetic code LinkageIdentification of disease gene
Determining the gene structure /gene protein
Mutation spectrum
Correlation to manifestationgenotype / phenotype
Gene testing
(Therapy)
-
Array-CGH
En molekylr cytogenetisk metod fr att detektera frndringar i mngden genetiskt material (DNA).
Detektera deletioner / duplikationer
Detektera mikrodeletioner / mikroduplikationer som inte kan ses vid vanlig kromosomanalys
Detektions niv Kromosomanalys ~1Mb Array-CGH ~50kb (20x)