現(xiàn)代臨床病理學(xué)-206.0.0遺傳病理進展

浙江大學(xué)

課程臨床病理學(xué)遺傳病理學(xué)臨床應(yīng)用進展Ming

Qi

祁鳴,PhD,

FACMG,Dip

ABMG浙江大學(xué)醫(yī)學(xué)院附屬第一醫(yī)院遺傳與浙江大學(xué)沃森 組科學(xué)華大組醫(yī)學(xué)中心羅切斯特大學(xué)醫(yī)學(xué)中心病理系哈佛醫(yī)學(xué)院-PARTNER遺傳與組學(xué)中心2016-10-10What

is

Diseasedis·ease

(d?-zēz')n.A

pathological

condition

of

a

part,

organ,

or

system

of

anorganism

resultingfromvarious

causes,

such

as

infection,

geneticdefect,

or

environmental

stress,and

characterized

by

an

identifiable

group

ofsigns

or

symptoms.A

condition

or

tendency,

as

of

society,

regarded

as

abnormal

and

harmful.Obsolete.

Lack

of

ease;

trouble.Part

of

your

job

is

to

build

good

experience

inassociating

symptomsand

signs

with

disease

names.

This

isan

art

and

you

have

tobegoodat

it.Once

you e

proficient,

you

will

think:What

caused

the

disease?

Endogenous

reaction/defect

orexogenousfactor(s)How diagnose

itWhat

is

the

molecular

basis

for

the

disease?Why

do

diseases

behave

differently

in

different

people?醫(yī)學(xué)的新發(fā)展精準(zhǔn)醫(yī)療組學(xué)藥物

組學(xué)罕見遺傳病的生殖

組學(xué)臨床 組學(xué)信息系統(tǒng)Understandingthe

Structure

ofGenomesUnderstandingthe

Biology

ofGenomesUnderstandingthe

Biology

ofDiseaseAdvancing

the

Science

ofMedicine1990-2003Human

Genome

Project2004-20102011-2020Beyond

2020Genomicplishments

AcrosssImproving

theEffectivenessofHealthcareCourtesy

from

Eric

Green,

Director,

NHGRI遺傳因素和環(huán)境因素在疾病中的作用單 疾病多因子疾病致病易感健康/疾病=+環(huán)境因素外傷環(huán)境肺癌 交通意外血友病 大腸癌 老年癡呆侏儒中風(fēng) 心血管疾病皮膚癌哮喘20165800（5000

genes）199061可以進行的疾病可以進行的疾病種類D:\ZJU\Hospital\Clinic\Disorders

that

can

be

gene

tested1-translated12605.doc行為異常Behavior

Disorder血液Blood腫瘤Cancer結(jié)締組織Connective

Tissue頜面部Craniofacial牙齒Dental耳Ear

內(nèi)

Endocrine眼Eye胃腸Gastrointestinal泌尿Genitourinary發(fā)育Growth耳聾Hearing

Loss/Deafne心臟Heart免疫Immune四肢Limb

Malformation肝Liver代謝Metabolic線粒體Mitochondrial早衰Premature

Aging肺Pulmonary腎Renal骨胳Skeletal皮膚毛發(fā)指甲Skin/Hair/Nails血管Vascular神經(jīng)NeurologicWhat

is

Genetic

Pathology?Pathology:

is

the

study

of

diseases.Molecular

biology:

the

study

of

molecules

in

biological

systems

thatare

responsible

for

normal

biological

traits

or

behaviors

i.e.:

DNAreplication,

transcription

and

translation

in

normalcells.Molecular

pathology:

an

evolving

field

that

examinesand

identifiesthe

molecules

involved

in

specific

diseases.

Integrates

knowledge

andtechniques

applied

in

molecular

biology

to

pathology.Genetic

Pathology:

the

study

of

genetics

that

examines

and

identifiest e(s)

involved

in

specific

diseases.

The

simple

concept

thatgenetic

disorders

involve

single

gene

defects

is

changing,

with

morecomplex

modes

of

genetic

inheritance

including

polygenic,multifactorial

(genes

interacting

with

the

environment),

unstable

DNA

and

epigenetic

mechanisms

(eg.

imprinting),

being

described.SUBSPECIALTIES

OFMOLECULAR

PATHOLOGYINHERITED

DISEASES

(GENETICS)Cystic

fibrosisSickle

cell

anemiaPredispositions

to

cancerINFECTIOUS

DISEASESBacteriaesFungiMolecular

Pathology:

RationaleClassical

pathologists

examine

tissue

sections

stained

with

Haematoxilinand

Eosin

(H&E)

and

otherstains,and

is

able

to

know

the

issues

origin,

organization

and

what

disease

it

represents.However,

this

is

anart

involving

human

skill,not

science.A

pathologistis

unable

to

define

the

molecules

and

how

they

interactto

produce

the

disease

represented

by

what

is

observedmicroscopically.

This

is

the

job

of

a

molecular

pathologist.The

molecular

pathologist

utilizes

techniques

from

molecular

biology

tostudy

differences

between

normal

and

diseased

tissue

at

the

molecularlevel,

so

that

the

specific

molecules

associated

with

the

disease

maybeidentified.We

work

as

members

of

multidisciplinary

teamWho

is

a

molecular

geneticist?

Clinical

geneticist?Molecular

BasisOf

DiseasesEnvironmentAnd

genesChanges

anEnzymee.g.

Phenylalanine

hydroxylaseSplice

site

mutation

leading

to

reduced

amountCausing

phenylketonuriaChanges

an

Enzyme

inhibitore.g.

1-AntitrypsinMissense

mutation

thatimpair

secretion

from

liverTo

serum

causing

Emphysema

and

Liver

diseaseChanges

areceptore.g.

Low

density

lipoprotein

receptorDeletion

or

point

mutation

that

reduce

synthesis,Or

transportto

the

cell

surface

or

binding

to

lowdensity

lipoproteinCausing

Familial

hypercholesterolemiaChange

a

transport

or

carrier

protein1.e.g.

HaemoglobinMutations

in

splice

sites

(commonest)

leading

toReduced

-globin.causing

-Thalassemia

in-Thalassemia

the

-globin

gene

is

usually

deleted2.e.g.

Cystic

fibrosis

transmembrane

conductanceRegulator.

Deletions

or

point

mutation

causingCystic

fibrosis.Changes

in

Hemostasise.g.

Factor

VIII

deletions,

insertions,

nonsenseMutation

reduce

synthesis

or

abnormal

factor

VIIICausingHemophilia

A.Changes

in

structuralProteins1.e.g.

collagen,

DeletionsOr

point

mutation

thatProduce

reduced

amountOf

normal

collagen

orNormal

amounts

of

mutantCollagen.

CausingOsteogenesis

imperfecta2.e.g

cell

membrane

FibrillinMissense

mutations

causingMarfan

syndromeOr

deletion

of

dystrophin

geneCausing

Duchene

muscularDystrophyGrowth

regulatione.g.Rb

causingRetinoblastoma

etcDiagnosis:Looking

at

the

disease

from

the

small

molecules

point

of

viewElucidates

the

causes

of

the

disease

( es,hereditary,disruptions

of

the

normal

control

processes,

such

as

the

cell-cycle,

apoptosis

etc…)Provides

a

more

comprehensiveunderstanding

of

a disease,

it’snatural

history,

and

progression.Provides

an

understanding

of

the

overall

complexity

of

thedisease.Prognosis:–

Associateprobablefic

molecules

or

a

set

of

molecules

withthee

of

adisease.Treatment– Enables

new

treatment

modalities

for

specific

diseases.

Theconcept

of

custom/tailored

therapyRelevance

of

Molecular

PathologyGenetic

Cardiovascular

DiseasesIsolatedFamiliarMultiple

abnormalMultiple

abnormal,

recognizable

syndromeGene

Testing

of

Cardiovascular

Diseases1055

Diseases

can

be

DNAtested(7-16-2004,GeneReview/Tests)–

725–

330Clinical

serviceResearch

onlyHundreds

of

geneticcardiovascular

diseasesdefined500

relatedgenes

identified200(161+40)

disease

genes

testableCardiovascular

DiseasesHypertensionHypertrophic

cardiomyopathyCardiac

arrhythmiasLipoprotein

disordersReactive

oxygen

species

and

atherosclerosisMyocardialinfarctionAcute

coronary

syndromesHeart

failureCardiac

transplant

rejectionHemostasis

and

thrombosisPeripheral

arterial

diseasesCongenital

heartdiseasesPerioperative

and

procedural

medicineCardiovascular

DiseasesHypertensionHypertrophic

cardiomyopathyCardiac

arrhythmiasLipoprotein

disordersReactive

oxygen

species

and

atherosclerosisMyocardialinfarctionAcute

coronary

syndromesHeart

failureCardiac

transplant

rejectionHemostasis

and

thrombosisPeripheral

arterial

diseasesCongenital

heartdiseasesPerioperative

and

procedural

medicine高血壓病縮壓持續(xù)大于或等于140毫米

柱，舒張壓持續(xù)大于或等于90毫米

柱。臨床表現(xiàn)：輕者：頭痛，頭暈，頭脹，頸部扳住感，耳鳴、眼花、健忘、失眠，煩悶，乏力，四肢麻木，心悸等。嚴(yán)重者：會引起心力衰竭、腦溢血和腎功能衰竭等，甚至

。HypertensionBPGene

2+/-Gene

3+/-Body

massAgeDietsexEnvironmentGene

1+/-Susceptibility

genesSusceptibility

genesSusceptibility

genesSusceptibility

genesSusceptibility

genesRare

Forms

of

Monogenic

HypertensionLiddle’s

syndromeGordon’s

syndromeGlucocorticoid-remediablealdosteronismCongenital

adrenal

hyperplasiaLiddle’s

syndrome(pseudoaldosteronism)Autosomal

dominanthypertension

associated

with

low

plasma

renin

activity,metabolicalkalosis

due

to

hypokalemia,

and

hypoaldosteronism(low

secretion

ofaldosterone

醛固酮).one

of

several

conditions

known

as

pseudohyperaldosteronism.begins

in

infancy.abnormal

kidney

function,

with

excess

reabsorption

of

sodium

and

lossof

potassium

from

the

renal

tubule,caused

by

mutation

at

PPPxY

motif

of

the

beta

or

gamma

subunit

of

anepithelial

sodium

channel

(ENaC)

gene

at

16p13-p12

locus.treated

with

a

combination

of

low

sodium

diet

and

potassium-sparingdiuretic

drugs

(e.g.,

amiloride).Gordon’s

syndrome(Type

2

pseudoaldosteronism)Symptoms:short

stature,

in lectual

impairment,

dental

abnormalities,muscle

weakness,

severe

hypertension

by

the

third

decade

of

life,high

blood

potassium,

hyperchloremic

metabolic

acidosis,

lowaldosterone

level,

low

blood

renin

level,

hypervolemia,hyperkalemia,normal

renal

function.AD,

mutations

of

WNK1and

WNK4

(members

of

a

family

of

serine-threonine

kinases),

gain

of

function

and

increased

co-transporteractivity,

excessive

chloride

and

sodium

reabsorption,

and

volumeexpansion.Rx:

either

alow-sa iet

or

thiazide

diuretics,

aimed

at

decreasingchloride

intake

and

blocking

Na-Cl

co-transporter

activity.Glucocorticoid

Remediable

Aldosteronism,

GRA(familial

hyperaldosteronism

type

I)autosomal

dominant,

earlyonset

of

moderateto

severe

sal sitive

form

of

low

reninhypertension,

persistent

hyperaldosteronism,high

incidence

ofpremature

cerebrovascularevents.

rapid

suppression

of

aldosterone

byexogenous

glucocorticoid

(dexamethasone)administration.a

chimericgeneis

created

by

misalignment

ofchromatids

and

unequal

crossin er

betweenCYP11B1

(codes

for

11β-hydroxylase)

andCYP11B2

(codes

for

aldosterone

synthase),two

genes

that

reside

within

a

30-kilobasestretch

on

chromosome8.the

resulting

chimeric

gene

encodes

aproteinthat

has

aldosterone

synthase

enzymaticactivitybut

is

regulated

by

ACTH

rather

thanangiotensi

.Dx:both

dexamethasoneadministration

andgenetictesting

are

of

importance

inmaking

diagnosis.Rx:

glucocorticoids,

sodium-restricted

dietCongenital Adrenal

HyperplasiaAndrogen

excess

and

hypertension11

-hydroxysteroid

dehydrogenasemutatedHypertensionBPGene

2+/-Gene

3+/-Body

massAgeDietsexEnvironmentGene

1+/-Susceptibility

genesSusceptibility

genesSusceptibility

genesSusceptibility

genesSusceptibility

genesHypertensionPredispositionsusceptibility

genes

(by

association

studies,>150,http:/

/genome/candidates/candidates.html)Development“bad

gene”

in“bad

environment”salt

susceptibility,

stress,

climate,

obesityHypertension

Susceptibility

GenesApolipoproteinsChannels

and

TransportersCytoskeletal

and

Adhesion

MoleculesEndothelinsFat

and

LipidRegulationGlucose

RegulationGrowth

Factors

and

HormonesHypothalamus-Pituitary

AxisIntracellular

MessengersKallikrein-Kinin

pathwayNatriuretic

PeptidesRenin-Angiotensin-Aldosterone

pathwaySteroidsSympathetic

Nervous

SystemThromboxanes

and

ProstaglandinsMiscellaneousAngiotensi (Ang

II)

generatedin

the

afferent

arteriole

interactswith

AT1

receptors

on

cellularcomponents

of

the

nephronAngiotensinogenAng

IACEReninAng

IIAT1R=

AT1

Receptor抗高血壓藥作用點-BlockersCCBs*DiureticsACE

InhibitorsAT1Blockersa-Blockersa2-AgonistsCCBsDA1

AgonistsDiureticsSympatholyticsinoe.rs高血壓外周血管阻力org=心臟輸出量

X*

=

non-dihydropyridine

CCBsCardiovascular

DiseasesHypertensionHypertrophic

cardiomyopathyCardiac

arrhythmiasLipoprotein

disordersReactive

oxygen

species

and

atherosclerosisMyocardialinfarctionAcute

coronary

syndromesHeart

failureCardiac

transplant

rejectionHemostasis

and

thrombosisPeripheral

arterial

diseasesCongenital

heartdiseasesPerioperative

and

procedural

medicine惡性室性心律失常及心臟性猝死SADS,

or

sudden

arrhythmic

death

syndrome惡性室性心律失常及心臟性猝死是心血管的重大疾病。

心肌離子通道 突變（long

QT

syndrome,Brugada

syndrome）和肥厚性心肌病(hypertrophic

cardiomyopathy)是導(dǎo)致惡性室性心律失常及心源性猝死的兩種常見類型。在

，前者

約為1/2000，后者甚至更高達(dá)1/500。我國目前尚缺乏惡性室性心律失常及心臟性猝死的詳盡流行病學(xué)資料。惡性室性心律失常及心臟性猝死發(fā)病前往往癥狀不明顯，普通臨床 不易檢測，難以預(yù)防，猝死

也常常無法確定真正原因，高危家庭成員無法有效預(yù)防。Hank

Gathers(February

11,

1967

in

Philadelphia

–

March

4,

1990

in

Los

Angeles)Loyola

Marymount大學(xué) 球員在 的大學(xué)籃球聯(lián)賽中因肥厚性心肌病死于賽場上

.Sad

HistoryHank

Gathers

Loyola

Marymount

star

died

March

4,1990,

aftercollapsing

during

West

Coast

Conferencetournament

semifinal

game.Reggie

Lewis

Boston

Celtics

guard

died

July

27,

1993,while

practicing

at

BrandeisUniversity.Conrad

McRae

FormerSyracuse

University

basketballplayer

died

July

10,

2000,

while

practicing

with

OrlandoMagic's

entry

in

the

Southern

California

Pro

SummerLeague.Anthony

Bates

Kansas

State

football

player

died

July

31,2000,

after

sufferinga

heartattack

during

a

car

accident.Thomas

Herrion

San

Francisco

49er

died

Aug.

20,

2005,after

exhibition

gamein

Denver.肥厚性心肌病（

HCM

）臨床特征心肌

變，表現(xiàn)心肌異常肥厚， 不能舒張，且不是因高血壓或主動脈瓣肥厚。HCM組織學(xué)改變?yōu)樾募》屎?、心肌纖維排列紊亂。細(xì)胞與細(xì)胞之間的排列紊亂。大多數(shù)

常癥狀不明顯，只是在

親友普查時發(fā)現(xiàn)，最常見癥狀：(1)

呼吸 。90%有癥狀都有繼發(fā)性舒張功能紊亂、左室充盈

，左房、肺靜脈壓

升高。(2)

心絞痛見于75%有癥狀

。因心肌供氧與氧需求之間不平衡引起。(3)

昏厥：因勞累

搏出量不足，或因心律失常。常見的心律失常有特發(fā)性房顫，非持續(xù)

性室性心動過速等。猝死通常是青少年患者，暫無癥狀

患者的首發(fā)癥狀，也是引起年輕運動員猝死最常見的原

因。HCM呈現(xiàn)常

顯性遺傳，具有遺傳異質(zhì)性。高達(dá)1/500-1/1000，是危害人們生命和健康的重大疾病。HCM

as

adisease

of

theereHCM

Clinical

FeaturesLeft

Ventricular

Hypertrophy

(LVH)Electrocardiograph

(EKG)

changesShortness

of

breath,

chest

pain,

exerciseintoleranceIncreased

risk

of

Sudden

Cardiac

Death(SCD)(variable,

and

may

not

occur

in

every

patient)Molecular Genetics

of

HCMAutosomal

dominantThe

presence

of

a

pathogenic

mutation

inone

copy

of

the

above

listed

genes

issufficient

to

cause

HCM.Children

of

an

affected

individual

with

an

identified

pathogenic

mutation

have

a50%

risk

of

inheriting

the

same

mutation.Epidemiology

of

HCM1/500

to

1/1000Males

and

females

are

affected

in

equalfrequencyNo

known

racial

predilection.Test

Indications

of

HCMPatients

with

clinical

features

of

HCM.Parents,

siblings,

and

possibly

children

ofa

patient

diagnosed

with

a

mutation

inone

of

the

HCM

genes.Prenatal

testing

when

a

parent

or

child

isdiagnosed

with

HCM

and

has

anidentified ere

gene

mutation.Test es

of

HCMThe

detection

of

a

pathogenic

mutationwill

offer

a

definitive

diagnosis

for

anaffected

patient.Referral

to

a

cardiology

center

withexpertise

in

the

management

ofhypertrophic

cardiomyopathy

is

highlymended.帶有缺陷并非世界Eddie

Curry, NBA前芝家哥公牛隊球員.

兩次發(fā)生心率異常,球隊要求他進行 。Dr.

David

Cannom,

atUCLA為他開了綠燈。The

NBA

Is

the League

to

BeginStandardized

Cardiac

ScreeningFiled

under:

News/Events

-

Posted

on

Sunday,

September17th,

2006

@

4:17

pmCenter

for

Genetics

&

GenomicsHCMHCM-AGeneNameOMIM#LocusMYH7myosin,heavy

chain

716076014q12MYBPC3myosin-binding

protein

c,

cardiac60095811p11.2TNNT2troponin

t2,

cardiac1910451q32TNNI3troponini,

cardiac19104419q13.4TPM1tropomyosin

119101015q22.1HCM-BGeneNameOMIM#LocusACTCactin,

alpha,cardiacmuscle10254015q14MYL2myosin

regulatory

light

chain16078112q23-q24.3MYL3myosinessentiallight

chain,

cardiac1607903pHCMHCM-A:

MYH7,

MYBPC3,

TNNT2,

TNNI3,TPM1HCM-B:

ACTC,

MYL2,

MYL3Unexplained

Cardiac

Hypertrophy(Danon

disease,

Glycogen

storagecardiomyopathy):

LAMP2

and

PRKAG2Cardiovascular

DiseasesHypertensionHypertrophic

cardiomyopathyIon

channel

related

cardiac

arrhythmiasLipoprotein

disordersReactive

oxygen

species

and

atherosclerosisMyocardialinfarctionAcute

coronary

syndromesHeart

failureCardiac

transplant

rejectionHemostasis

and

thrombosisPeripheral

arterial

diseasesCongenital

heartdiseasesPerioperative

and

procedural

medicine17歲青運會游泳冠軍慶文怡猝死1、重視體檢2、合理膳食3、減肥減重4、心理平衡5、適量運動6、戒煙限酒？預(yù)防記住這六招父母悲痛萬分，不做尸檢、讓孩子盡快安息長QT間期綜合征/BRUGADA綜合征等心臟電生理系統(tǒng)

:

心跳后需要更長時間恢復(fù)-->快速紊亂心律(torsade

de

pointes)突然失去知覺(syncope)猝死遺傳性(>

1/5,000)或后天藥物誘發(fā)心電圖ECG(EKG)正常QT:400

mSec長

QT: >

450mSecAutosomal

Dominant

(Romano-Ward

Syndrome)Isolated

susceptibility

to

ventricular

arrhythmia,

normal

hearingAutosomal

Recessive

(Jervell

and

Lange-NielsenSyndrome)LQT

plus

sensorineural

hearinglossKvLQT1KCNE1

(minK)homozygous,compound

heterozygoushomozygousGenetics

of

Long

QT

SyndromeNa+

current(LQT3,

Brugadasyndrome).Transient

outward

K+

currentUltra-rapid

component

of

thedelayed

rectifier

K+

currentRapid

component

of

delayedrectifier

K+

current(LQT2

+

LQT6)Slow

component

of

the

delayedrectifier

K+

current(LQT1

+

LQT5)ICa(L):L-type

Ca2+

currentInwardly

rectifying

K+

current(Andersen

syndrome)心肌跨膜電位INa:Ito:IKur:IKr:INaI(IKur)to

IIKr

KsICa(L)IKirIKs:IKir:什么因素會誘發(fā)LQTS?ExerciseEmotional

excitementsSleepDrugsLQTS國際登記處和羅切斯特大學(xué)遺傳與學(xué)組醫(yī)International

LQTS

RegistryEstablished

by

Dr.

Moss

in

1979.To

date,

1206

proband-identified

families

have

been

enrolled.Almost

all

important

findings

on

LQTS

directly

came

from

orcollaborated

with

this

registry.LQTS

Molecular

Genetics

LaboratoryEstablished

in

the

Fall

of

1999.>

2000

samples

are

collected

andmutationalMany

novel

mutations

have

been

identified.Platform

for

genotype-phenotype

co-relationship

studies,

identificationof

newLQT

genes

and

modifier

genes.LQTS

Mutations

byType(from

Splawski

et

al

Circulation,

2000.102:1178)LQTS

Mutations

byPosition(from

Splawski

et

al

Circulation,

2000.102:1178)Schematic

of

KvLQT1

and

Locations

ofLQT1-associated

MutationsExonNo.

of

familiesS6,

C-terP,

S6S5,

PoreS4/S5S2,

S2/S3(modified

from

Splawski

et

al

Circulation,

2000.

102:1178)PositionSchematic

of

HERG

and

Locations

of

LQT2-associatedMutationsPosition

ExonN-ter(modified

from

Splawski

et

al

Circulation,

2000.102:1178)No.

of

familiescNBDS5,

P,S6Schematic

of

SCN5A

and

Locations

of

LQT3-associatedMutationsNo.

of

familiesExon(from

Splawski

et

al

Circulation,

2000.

102:1178)PositionDIV/S3/S4/C-terDIII/DIVIncreased

Risk

of

Arrhythmic

Events

in

LQTS

with

Mutationsin

the

Pore

Region

of

HERGPotassium

Channel(Moss

et

al,

Circulation,

2002;

105:749)n=

34

(14

mutations)n=

54

(14

mutations)n=

91

(12

mutations)Reduced

Penetrance

of

the

LQTSonestudy

reported

that

33%

of

clinically

unaffected

family

members

in

kindredscontaining

a

varietyof

LQTS

mutations

were

found

to

be

gene

carriers

.(Priori,

et

al,

Circulation,

1999.

99:

529)Molecular

GeneticsofLong

QTSyndromeAndAllelic

DiseasesDisease

Allelic

to

Long

QT

Syndrome

1Atril

fibrillation:-rapid

and

irregular

activation

ofatrium-thrombolism-tachycardia-mediated

cardiomyopathy-heart

failure-ventricular

arrhythmia-<

1%

in

youngadult,

>5%

in

those

over

65years

old-can befamilialMolecular

Pathology:Long

QT

Syndrome

1

vs

Atril

FibrillationReduced

or

Loss

of

Activity Increased

Activity(Chen,

at

al

Science

299:251,

2003)Diseases

Allelic

to

Long

QT

Syndrome3Brugada

syndrome

(BS):inherited

arrhythmogenic

diseaseST-segmen evation

on

ECGventricular

fibrillationincreased

cardiac

sudden

deathSudden

unexplained

nocturnal

death

syndrome

(SUNDS)similar

to

BSfound

insoutheast

Asiaincreased

cardiac

sudden

death

during

sleepProgressive

cardiac

conduction

system

disease

(PCCD)similar

to

BSconduction

slowing

without

ST-segmen evation

on

ECGSchematic

of

SCN5A

and

Locations

of

LQT3,

BS,

andPCCD

Mutations(modified

from

Splawski

et

al

Circulation,

2000.102:1178)LQT3BS

PCCDSUNDS?K1500ysis

of

different

technologiesWomen

with

LQTS

have

a

reduced

risk

for

cardiac

events

during

pregnancy,

but

an

increasedrisk

during

the

9-month

postpartum

period,especially

among

women

with

the

LQT2

genotype.Beta-blockers

were

associated

with

a

reduction

incardiac

events

during

the

high-risk

postpartum

time

period.ysis

of

specific

eventysis

of

different

ages

and

gendersthe

timing

and

frequency

of

syncope,

QTcprolongation,

and

sex

were

predictive

ofrisk

foraborted

cardiac

arrest

and

sudden

cardiac

deathduring

adolescence.–

5-12y M

>

F; 13-20

y

M

=

FAmong

patients

with

recent

syncope,

-

blocker

treatment

was

associated

with

reduced

risk.The

severity

of

LQTS

in

adulthood

can

be

risk

stratifiedwith

information

regarding

genotype,

gender,

QTcduration,

and

history

of

cardiac

events.– Female

gender,

corrected

QT

(QTc)

interval,

LQT2

genotype,

andfrequency

of

cardiac

events

before

age

18

years

wereassociatedwith

increased

risk

of

having

any

cardiac

events

between

sof

18

and

40

years.

Female

gender,

QTc

=

500

ms,

and

interimsyncopal

events

during

follow-up

after

age

18

years

significantlyincreased

risk

of

life-threatening

cardiac

events

in

adulthood.Beta-blockers

effectively

(60%)

reduce

but

do

noteliminate

the

risk

of

both

syncopal

andlife-threateningcardiacevents

in

adult

patients

with

mutation-confirmedLQTS.ysis

of

different

genesysis

of

differentpopulationsCardiovascular

DiseasesHypertensionHypertrophic

cardiomyopathyCardiac

arrhythmiasLipoprotein

disordersReactive

oxygen

species

and

atherosclerosisMyocardialinfarctionAcute

coronary

syndromesHeart

failureCardiac

transplant

rejectionHemostasis

and

thrombosisPeripheral

arterial

diseasesCongenital

heartdiseasesPerioperative

and

procedural

medicineCongenital

heart

diseases:

Down’ssyndrome唐氏綜合征面容特殊，絕大多數(shù)為嚴(yán)重智能

，常伴有多種臟器的異常-消化

畸形，如

性食道閉鎖癥，十二指腸狹窄，鎖肛等-

性心臟病，患病比率高達(dá)40%，尤其是心內(nèi)膜不全比例較高，通常如果不進行早期治療會有致命

。近白內(nèi)障，患病率為2%急性白血病，患病率為1%環(huán)軸間接不穩(wěn)定性，患病率2-3%甲狀腺疾病，患病率3%點頭癲癇，患病率10%一時性骨髓異常增生癥眼異常，由角膜，水晶體異常視，遠(yuǎn)視，亂視等-浸出性中耳炎，容易在內(nèi)耳積蓄液體耳炎，影響聽覺Identification

of

t e

Jagged1

responsible

forAlagille

Syndromeintrahepatic

cholestasis(bile

duct

blockage)congenital

heart

diseaseskeletal

and

ocular

abnormalities(Nature

Genetics

16:243)Jagged1,

a

ligand

for

Notch1

transmembrane

receptorCardiovascular

DiseasesHypertensionHypertrophic

cardiomyopathyCardiac

arrhythmiasLipoprotein

disordersReactive

oxygen

species

and

atherosclerosisMyocardialinfarctionAcute

coronary

syndromesHeart

failureCardiac

transplant

rejectionHemostasis

and

thrombosisPeripheral

arterial

diseasesCongenital

heartdiseasesPerioperative

and

procedural

medicine心臟

（AHA）

推介3項疾病風(fēng)險易感(2007年佛羅里達(dá)奧蘭多年會)房顫導(dǎo)致中風(fēng)風(fēng)險易感

，心肌梗死風(fēng)險易感

，和2型

風(fēng)險易感

。這些檢測的研發(fā)均基于大樣本、多族群的

組醫(yī)學(xué)研究，

于國際最

的醫(yī)學(xué)學(xué)術(shù)期刊，并經(jīng)多方驗證確認(rèn)的研究成果房顫導(dǎo)致中風(fēng)風(fēng)險易感，進而選該項檢測目的在于檢出未知房顫擇最合適的預(yù)防中風(fēng)的治療干預(yù)。房顫是心律異常的最常見類型和心源性中風(fēng)的首要原因20%的中風(fēng)為心源性，致病率和致死率最高的亞型人們往往并不察覺它們患有間歇性房顫，即使標(biāo)準(zhǔn)的24-48小時的住院觀察也常易漏檢漏診–

4q25的2007:

Vol

448,可幫助檢出房顫(Nature:10.1038/nature06007).–

WARFARIN能有效治療房顫，進而預(yù)防心源性中風(fēng)適用檢測人群：疑是房顫

或普通體檢者心肌梗死風(fēng)險易感該項檢測目的在于檢出未知心肌梗死

，進而選擇最合適的預(yù)防心肌梗死的治療干預(yù)。心血管疾病是人類生命頭號

，而心肌梗死占其一半以上心肌梗死的致病率和致死率最高，以及健保系統(tǒng)的巨大財政負(fù)擔(dān)。人們往往并不察覺它們患有心肌梗死9號

的

可幫助檢出心肌梗死(Science,2007;316:1491-93;

Science,

2007;

316:1491-93

)了解心肌梗死的遺傳因素可以幫助

重視改變不良生活方式：戒煙、減肥、合理膳食能有效治療預(yù)防或普通體檢心肌梗死適用檢測人群：疑是心肌梗死者2型

風(fēng)險易感，進而選擇該項檢測目的在于檢出未知2型最合適的預(yù)防治療干預(yù)。–

工業(yè)社會里，II型

的

正在迅速升高。估計，僅在

就有超過兩千萬的

患者。大多數(shù)患有II型

的人、或許

患者的三分之一從不知道他們已經(jīng)患病。另外，超過五千萬的

人屬于患者中的三分之一很可能在三年內(nèi)轉(zhuǎn)變成II型前期。這些，三分之的情況下恢一仍然保持在復(fù)正常的血糖水平（–

10號

的前期，另外三分之一在不預(yù)防計劃研究組織）可幫助檢出2型–在II型的發(fā)