现代临床病理学-206.0.0遗传病理进展

浙江大学

课程临床病理学遗传病理学临床应用进展Ming

Qi

祁鸣,PhD,

FACMG,Dip

ABMG浙江大学医学院附属第一医院遗传与浙江大学沃森 组科学华大组医学中心罗切斯特大学医学中心病理系哈佛医学院-PARTNER遗传与组学中心2016-10-10What

is

Diseasedis·ease

(dĭ-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?医学的新发展精准医疗组学药物

组学罕见遗传病的生殖

组学临床 组学信息系统Understandingthe

Structure

ofGenomesUnderstandingthe

Biology

ofGenomesUnderstandingthe

Biology

ofDiseaseAdvancing

the

Science

ofMedicine1990-2003Human

Genome

Project2004-20102011-2020Beyond

2020Genomicplishments

AcrosssImproving

theEffectivenessofHealthcareCourtesy

from

Eric

Green,

Director,

NHGRI遗传因素和环境因素在疾病中的作用单 疾病多因子疾病致病易感健康/疾病=+环境因素外伤环境肺癌 交通意外血友病 大肠癌 老年痴呆侏儒中风 心血管疾病皮肤癌哮喘20165800（5000

genes）199061可以进行的疾病可以进行的疾病种类D:\ZJU\Hospital\Clinic\Disorders

that

can

be

gene

tested1-translated12605.doc行为异常Behavior

Disorder血液Blood肿瘤Cancer结缔组织Connective

Tissue颌面部Craniofacial牙齿Dental耳Ear

内

Endocrine眼Eye胃肠Gastrointestinal泌尿Genitourinary发育Growth耳聋Hearing

Loss/Deafne心脏Heart免疫Immune四肢Limb

Malformation肝Liver代谢Metabolic线粒体Mitochondrial早衰Premature

Aging肺Pulmonary肾Renal骨胳Skeletal皮肤毛发指甲Skin/Hair/Nails血管Vascular神经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高血压病缩压持续大于或等于140毫米

柱，舒张压持续大于或等于90毫米

柱。临床表现：轻者：头痛，头晕，头胀，颈部扳住感，耳鸣、眼花、健忘、失眠，烦闷，乏力，四肢麻木，心悸等。严重者：会引起心力衰竭、脑溢血和肾功能衰竭等，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抗高血压药作用点-BlockersCCBs*DiureticsACE

InhibitorsAT1Blockersa-Blockersa2-AgonistsCCBsDA1

AgonistsDiureticsSympatholyticsinoe.rs高血压外周血管阻力org=心脏输出量

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恶性室性心律失常及心脏性猝死SADS,

or

sudden

arrhythmic

death

syndrome恶性室性心律失常及心脏性猝死是心血管的重大疾病。

心肌离子通道 突变（long

QT

syndrome,Brugada

syndrome）和肥厚性心肌病(hypertrophic

cardiomyopathy)是导致恶性室性心律失常及心源性猝死的两种常见类型。在

，前者

约为1/2000，后者甚至更高达1/500。我国目前尚缺乏恶性室性心律失常及心脏性猝死的详尽流行病学资料。恶性室性心律失常及心脏性猝死发病前往往症状不明显，普通临床 不易检测，难以预防，猝死

也常常无法确定真正原因，高危家庭成员无法有效预防。Hank

Gathers(February

11,

1967

in

Philadelphia

–

March

4,

1990

in

Los

Angeles)Loyola

Marymount大学 球员在 的大学篮球联赛中因肥厚性心肌病死于赛场上

.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

）临床特征心肌

变，表现心肌异常肥厚， 不能舒张，且不是因高血压或主动脉瓣肥厚。HCM组织学改变为心肌肥厚、心肌纤维排列紊乱。细胞与细胞之间的排列紊乱。大多数

常症状不明显，只是在

亲友普查时发现，最常见症状：(1)

呼吸 。90%有症状都有继发性舒张功能紊乱、左室充盈

，左房、肺静脉压

升高。(2)

心绞痛见于75%有症状

。因心肌供氧与氧需求之间不平衡引起。(3)

昏厥：因劳累

搏出量不足，或因心律失常。常见的心律失常有特发性房颤，非持续

性室性心动过速等。猝死通常是青少年患者，暂无症状

患者的首发症状，也是引起年轻运动员猝死最常见的原

因。HCM呈现常

显性遗传，具有遗传异质性。高达1/500-1/1000，是危害人们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.带有缺陷并非世界Eddie

Curry, NBA前芝家哥公牛队球员.

两次发生心率异常,球队要求他进行 。Dr.

David

Cannom,

atUCLA为他开了绿灯。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岁青运会游泳冠军庆文怡猝死1、重视体检2、合理膳食3、减肥减重4、心理平衡5、适量运动6、戒烟限酒？预防记住这六招父母悲痛万分，不做尸检、让孩子尽快安息长QT间期综合征/BRUGADA综合征等心脏电生理系统

:

心跳后需要更长时间恢复-->快速紊乱心律(torsade

de

pointes)突然失去知觉(syncope)猝死遗传性(>

1/5,000)或后天药物诱发心电图ECG(EKG)正常QT:400

mSec长

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)心肌跨膜电位INa:Ito:IKur:IKr:INaI(IKur)to

IIKr

KsICa(L)IKirIKs:IKir:什么因素会诱发LQTS?ExerciseEmotional

excitementsSleepDrugsLQTS国际登记处和罗切斯特大学遗传与学组医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唐氏综合征面容特殊，绝大多数为严重智能

，常伴有多种脏器的异常-消化

畸形，如

性食道闭锁症，十二指肠狭窄，锁肛等-

性心脏病，患病比率高达40%，尤其是心内膜不全比例较高，通常如果不进行早期治疗会有致命

。近白内障，患病率为2%急性白血病，患病率为1%环轴间接不稳定性，患病率2-3%甲状腺疾病，患病率3%点头癫痫，患病率10%一时性骨髓异常增生症眼异常，由角膜，水晶体异常视，远视，乱视等-浸出性中耳炎，容易在内耳积蓄液体耳炎，影响听觉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心脏

（AHA）

推介3项疾病风险易感(2007年佛罗里达奥兰多年会)房颤导致中风风险易感

，心肌梗死风险易感

，和2型

风险易感

。这些检测的研发均基于大样本、多族群的

组医学研究，

于国际最

的医学学术期刊，并经多方验证确认的研究成果房颤导致中风风险易感，进而选该项检测目的在于检出未知房颤择最合适的预防中风的治疗干预。房颤是心律异常的最常见类型和心源性中风的首要原因20%的中风为心源性，致病率和致死率最高的亚型人们往往并不察觉它们患有间歇性房颤，即使标准的24-48小时的住院观察也常易漏检漏诊–

4q25的2007:

Vol

448,可帮助检出房颤(Nature:10.1038/nature06007).–

WARFARIN能有效治疗房颤，进而预防心源性中风适用检测人群：疑是房颤

或普通体检者心肌梗死风险易感该项检测目的在于检出未知心肌梗死

，进而选择最合适的预防心肌梗死的治疗干预。心血管疾病是人类生命头号

，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，以及健保系统的巨大财政负担。人们往往并不察觉它们患有心肌梗死9号

的

可帮助检出心肌梗死(Science,2007;316:1491-93;

Science,

2007;

316:1491-93

)了解心肌梗死的遗传因素可以帮助

重视改变不良生活方式：戒烟、减肥、合理膳食能有效治疗预防或普通体检心肌梗死适用检测人群：疑是心肌梗死者2型

风险易感，进而选择该项检测目的在于检出未知2型最合适的预防治疗干预。–

工业社会里，II型

的

正在迅速升高。估计，仅在

就有超过两千万的

患者。大多数患有II型

的人、或许

患者的三分之一从不知道他们已经患病。另外，超过五千万的

人属于患者中的三分之一很可能在三年内转变成II型前期。这些，三分之的情况下恢一仍然保持在复正常的血糖水平（–

10号

的前期，另外三分之一在不预防计划研究组织）可帮助检出2型–在II型的发