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)