眼睛单基因疾病遗传咨询

眼睛单基因疾病的早期诊断与遗传咨询1.

遗传物质的存在遗传与分离规律显性遗传和隐性遗传规律X-连锁遗传规律核酸（nuclein（now

nucleic

acids））的发现核苷酸碱基（A

T

G

C

U)的发现遗传物质DNA与基因和染色体的联系（1944）DNA结构DNA测序HumanGenome

ProjectCompletedin2003,theHumanGenomeProject(HGP)wasa13-yearprojectcoordinatedbytheU.S.DepartmentofEnergyandtheNationalInstitutesofHealth.DuringtheearlyyearsoftheHGP,theWellcomeTrust(U.K.)becameamajorpartner;additionalcontributionscamefromJapan,France,Germany,China,and

others.identifyalltheapproximately20,000-25,000genesinhuman

DNA,determinethesequencesofthe3billionchemicalbasepairsthatmakeuphuman

DNA,storethisinformationin

databases,improvetoolsfordata

analysis,transferrelatedtechnologiestotheprivatesector,

andaddresstheethical,legal,andsocialissues(ELSI)thatmayarisefromthe

project.ThoughtheHGPisfinished,analysesofthedatawillcontinueformany

years.测序花费直线下降单基因疾病（polygenic

diseases)多基因疾病

(polygenic

diseases)光信号不可逆的视力下降甚至失明-3

-化学信号基因突变视觉形成RPE眼科临床检查病人主述，症状，体征，视力，眼底（镜，照相），血管造影，眼压，OCT，房角，视野，电生理（ERG)，角膜，眼轴，病理，房水，CT，MRI，实验室检查（血常规，生化，免疫，微生物等）…基因诊断……Ptosis(眼睑下垂）Mostcasesarein

syndromesAnumbersign(#)isusedwiththisentrybecausetheblepharophimosis-ptosis-intellectualdisabilitysyndrome(BPIDS)iscausedbyheterozygousmutationintheUBE3Bgene(608047)onchromosome12q23.Strabismus(斜视）Overall,esotropiaismorecommonthan

exotropia.先天性眼外肌纤维化congenital

fibrosis

of

extraocularmuscles-1(CFEOM1)iscausedbyheterozygousmutationintheKIF21Agene(608283)on

chromosome12q12CFEOM2(602078),anautosomalrecessivedisordercausedbymutationintheARIXgene(602753)onchromosome11q13,ischaracterizedbybilateralptosiswitheyesfixedinanexotropic

position.Nystagmus(眼球震颤)Anumbersign(#)isusedwiththisentrybecauseofevidencethatchildhood-onsetneurodegenerationwithopticatrophy(NDGOA)iscausedbyhomozygousmutationintheUCHL1gene(191342)onchromosome4p14.Onesuchfamilyhasbeen

reported.AformofautosomalrecessivenonsyndromicdeafnessdesignatedDFNB84A(613391),whichalsomapstochromosome12q21,iscausedbymutationinthePTPRQgene

(603317).Anumbersign(#)isusedwiththisentrybecauseofevidencethatX-linkedcongenitalnystagmus-1(NYS1)andinfantileperiodicalternatingnystagmus(XIPAN)arecausedbymutationintheFERMdomain-containing-7gene(FRMD7;300628)onchromosome

Xq26.OMIMmostcasesarein

syndromesCorneal

DystrophyFifteengenesoutofnineteen

lociKlintworthetal.OrphanetJournalofRareDisease

2009Klintworthetal.OrphanetJournalofRareDisease

2009Klintworthetal.OrphanetJournalofRareDisease

2009Klintworthetal.OrphanetJournalofRareDisease

2009ABCD共聚焦显微镜显示角膜呈糜烂状格子状角膜营养变性

(latticecorneal

dystrophy

)-TGFBI(exon4:c.C370T:p.R124C)先天性无虹膜伴晶体脱位先天性无虹膜合并白内障(congenital

aniridia

and

cataract)-PAX6对该家系进行测序扫描，发现PAX6新的突变；IIIIIIIV12123451234512白内障－最常见眼睛遗传病至少有35个基因先天性白内障家系

(autosomal

dominant

congenital

cataract)-GJA8对该家系进行测序扫描，发现GJA8新的突变；先天性白内障患者家系图林婴等《中华医学遗传学杂志》2008年

第1期

59-62页青光眼分类先天性青光眼原发性青光眼

开角性青光眼（POAG）（西方国家主要）

闭角性青光眼（PACG）（我国青光眼的一半以上）继发性青光眼混合性青光眼正常眼底图患者视乳头正常视乳头青光眼青光眼以周围视力丢失为主要临床特征青光眼基因GLC1A(1q23,MYOC)

（POAG),GLC3A

(2p21,

CYP1B1)

（先天性）,RIEG1

(4q25,

PITX2)(（先天性）),GLC1G(5q22,

WDR36)(POAG),IRID1

(6p25,FOXC1)

（先天性）,Nailpatellasyndrome(NPS)(9q34,LMX1B),GLC1E(10p15-p14,

OPTN)AN2(11p13,PAX6)LTBP2

(14q24.3)

（先天性）LTBP2:NM_000428:exon14:c.G2421A:p.W807XLTBP2unaffetedaffetedunaffetedaffetedCYP1B1:NM_000104:exon3:c.C1198T:p.P400S,CYP1B1青光眼突变家系视网膜组织结构视锥细胞

（Cone)：强光和颜色视杆细胞

(Rod)：暗视野和运动物体/retnet//retnet/https://sph.uth.t/retnet//retnet/Retinitis

Pigmentosa特点：双眼视网膜周围视野减弱或消失，暗视野功能减弱或消失，发病率1/3000。骨样色素沉着为其特征。视网膜色素变性（RP）-PRPF31LuF.etal.PLoSOne.2013Nov

11;8(11):e78274.对该家系进行测序扫描，发现PRPF31新的突变；JuvenileMacular

Dystrophy单纯性或原发性青少年黄斑变性疾病名称位点基因常染色体隐性STGD11p21-p13ABCA4常染色体显性STGD36q14ELOVL4AVMD,

PMD6q14RDSSTGD44q21PROM1BEST111q13VMD2SFD22q13-qterTIMP3DHRD2p16EFEMP1MCDR1/PBCRA6q11-q16.2unknownMCDR35q13.1-p15.3unknownMCDR414qunknownMCDR519q13unknownDCMD7p15unknownMacular

degeneration(MCDR3)

5p13.1-p15.33(MCDR4)14q(MCDR5)

19q13Michaelides,etal.InvestOphthalmolVisSci,2003.44(5):p.2178-83.Francisetal.BrJOphthalmol,2003.87(7):p.893-8.Yangetal.JMedGenet,2006.43(12):p.

e57.Pedigreesofautosomaldominantmaculardystrophy&segregationofaPROM1

mutationRetinaldegenerationasaconsequenceofmutantR373C

PROM1AnIndiaFamilywithRPcausedbymutant

PROM1Mawetal.HumanMolecularGenetics,2000,9(1)

27-34AconsanguineousPakistanifamilywithaPROM1mutationFunduspictures:RPand

MDZhangetal.HumanGenet(2007)

122:293-299PROM11726C>TmutationinthePakistani

familyZhangetal.HumanGenet(2007)

122:293-299PROM1wasexpressedinbothconeandrodphotoreceptorsatthebaseof

OSYangetal.2008JournalofClinical

InvestigationTransgenicmiceexpressingR373Chumanmutationshowprogressivedeteriorationof

ERGSElectronmicroscopyofPROM1transgenicmouserod

photoreceptorsYangetal.2008

JournalofClinical

InvestigationMislocalizationofmutantPROM1in

photoreceptorsHuman

PROM1

Mouse

Prom1

MergeCo-immunoprecipitationofPROM1/PCDH21,andproteolyticcleavageof

PCDH21Co-immunoprecipitationofPROM1andb-actinPROM1promotesgrowthofmembrane

processesModelofdisk

morphogenesisKleinman&Ambati,JCI,

2008视网青少年黄斑变性家系（

Stargardt

Disease）-ABCA4对该家系进行外显子测序分析，发现ABCA4新的突变；ZhouY.etalPLoSOne.2014Mar14;9(3):e91962.doi:

10.1371/journal.pone.0091962.Familialexudativeretinopathy

(FEVR)Thegrowthandruptureofabnormalbloodvessels(vascularization)intheouteredgesoftheretinacalledtheperipheral

region.Bloodvesselgrowthcanoccuratarapidandcontinuous

pace.Bleedingofthesebloodvesselscanleadtodraggingoftheretinacalledretinaltraction,andmayresultinscarringand/orretinaldetachmentduetothe

pullingofthe

retina.家族性渗出性玻璃体视网膜病变（FEVR）-TSPAN12对3个FEVR家系进行测序扫描，发现c.566G>A

(p.C189Y),

c.177delC(p.Y59fsX67)和c.C254T

(p.T85M).这三个FZD4新的致病突变；功能研究发现这三个突变导致TSPAN12没有活性，影响Norrin信号通路的激活。XuY,HuangL,LiJ,ZhangQ,FeiP,ZhuX,TaiZ,MaS,GongB,LiY,ZangW,ZhuX,ZhaoP,YangZ.NovelmutationsintheTSPAN12gene

inChinesepatientswithfamilialexudativevitreoretinopathy.MolVis.2014Sep

20;20:1296-306家族性渗出性玻璃体视网膜病变（FEVR）-LRP5活。对2个FEVR家系进行测序扫描，发现p.A422T

和

p.L540P

这两个FZD4新的致病突变；功能研究发现这二个突变导致LRP5没有活性，影响Norrin信号通路的激家系1 家系2FeiP,ZhangQ,HuangL,XuY,ZhuX,TaiZ,GongB,MaS,YaoQ,LiJ,ZhaoP,YangZ.IdentificationoftwonovelLRP5mutationsinfamilieswithfamilialexudativevitreoretinopathy.MolVis.2014Mar29;20:

395-409.巴尔得-别德尔综合征（

Bardet–Biedl

syndrome

）-BBS7对该家系进行关联分析，发现ABCA4新的突变；眼球缺损－先天性小眼球

(>27genes)只有眼球缺损PAX6

(MIM

607108),

SHH

(MIM600725),GDF3(MIM606522)RBP(MIM

180250)

27coloboma-associatedgenes,mutationsinCHX10(MIM142993),MAF(MIM177075),SOX2(MIM184429),OTX2(MIM600037)andRAX(MIM601881)withdiseasephenotypesoftheeyeincludingmicrophthalmia,cataractandmicroconea.学术论文：Am

J

Hum

Genet.

2012;90(1):40-8.

（影响因子11.2）发现一个新的视网膜缺损致病基因-ABCB6，在斑马鱼模型证实其功能模式和作用机制四、推广应用--PRD准确诊断及干预小儿视网膜病变基因诊断芯片在早期发现、鉴别诊断和产前诊断等方面成功应用四、推广应用--早期发现指导治疗视网膜母细胞瘤（RB）恶性程度极高，根据其病程进展可分为A-E五期