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Genotype-phenotypecorrelationin patientswithalbinism Alina VDumitrescu, MD University ofIowa March2016- FIRSTANNUALMIDWESTPEDIATRIC OPHTHALMOLOGYSYMPOSIUM Albinism • Albinismisadefectofmelaninproduction thatresultsinlittle orno pigmentintheskin,hair,andeyes. • Themostsevereformofalbinismisoculocutaneous albinism (OCA) • Ocularalbinism(OA)affectsonlytheeyes.Theskinandiris colorisusuallyinthenormalrangebutthere islackof pigmentintheretina • Hermansky-Pudlak syndrome (HPS)andChediak-Higashi syndromesareformsofOCAassociatedwithsystemicdefects 1 Geneticsofalbinism • Todatethereare15genesknowntocausevarioustypesof albinism • Onlyforaboutthepast5years,moleculargenetictestinghas beenavailable Oculocutaneous albinism • Anestimated1in20,000people worldwidearebornwith OCA. • Thecondition affectspeopleinallethnicgroups and geographicalregions. • Affectedindividualstypicallyhavevery fairskinandhair, increasedriskofskindamageandskincancers. • Nystagmus,photophobia, decreasedvision,reduced pigmentationoftheirisandtheretina,iristransillumination defects,fovealhypoplasiaandopticnerve abnormalitiesare present 2 Oculocutaneous albinism • OCAisinheritedinanautosomalrecessivepattern • OCA1 (TYRmutations),OCA2(P gene),OCA3(TYRP1 mutations)andOCA4 (SLC45A2mutations)genesare currently known tocauseOCA https://ghr.nlm.nih.gov/condition/oculocutaneous-albini sm Ocularalbinism • ThemostcommonformOA1,affectsatleast1in60,000 males.Theclassicsignsandsymptomsaremuchlesscommon infemales. • OAprimarilyaffectstheeyesbut skinbiopsyrevealsabnormal melanocytespresentinthesepatients. • Affectedindividualshavealightpigmentedirisandretinabut thecoloroftheskinandhairisnotsignificantlyaffected.They mayhave asomewhatlightercomplexion thanother membersoftheirfamily. • Severelyimpairedvisualacuity,nystagmus,strabismus, photophobia, abnormalitiesinvolvingtheopticnervesare present. 3 Ocularalbinism • OA1isinheritedinanX-linkedpattern. • OA1 (GPR143)geneiscurrently knowntocauseOA https://ghr.nlm.nih.gov/condition/ocular-albinism Hermansky-Pudlak syndrome • Isararedisorderinmostpopulations andisestimatedto affect1in500,000to1,000,000 individualsworldwide. • IsmorecommoninPuertoRico,particularlyinthe northwestern partoftheislandwhereabout 1in1,800 peopleareaffected. • AffectedindividualshaveOCA,coagulationdefects, pulmonary fibrosis,granulomatouscolitisandkidney failure. 4 Hermansky-Pudlak syndrome • Isinherited inanautosomalrecessivepattern • TodateatleastninegenesareassociatedwithHPS https://ghr.nlm.nih.gov/condition/hermansky-pudlak-syndrome Chediak-Higashisyndrome • Isararedisorder.About 200casesofthecondition havebeen reported worldwide. • AffectedindividualshaveOCAandimmunedeficiency, coagulationdeficitsandneurologicsymptomsincluding weakness, clumsiness,difficultywithwalking,andseizures 5 Chediak-Higashisyndrome • Isinherited inanautosomalrecessivepattern • MutationsintheLYST genearecurrently known tocausethe disease https://ghr.nlm.nih.gov/condition/chediak-higashi-syndrome Purpose • Toevaluatethecorrelationbetweenocularandsystemic phenotype withgenotype inpatientswithaclinicaldiagnosis ofalbinismthatunderwent moleculartesting. 6 Methods • IRBapproval • Aretrospectivechartreviewwasperformedonpatients presentingtoUIHC,since1980until2015,clinicallysuspected ofhavingalbinism. • Clinicalfeaturesandmoleculargeneticdiagnosiswere recorded andanalyzed. • Aclinicalscoringsystem0-5wasdeveloped forphenotypic analysis Clinicalscoring • Fovealhypoplasia – 1pct • Nystagmus– 1pct • DiffuseirisTIDs– 1pct • Vision20/25-20/40– 0.5pct • Visionlessthan20/40– 1pct • Opticnervessmall– 0.5pct • Opticnervesgrey– 0.5pct Min0- Max5 7 Results • 44patientswereidentifiedtohave hadclinicaldiagnosisof albinism. • Ofthese,42underwent genetictesting. • 15(36%)patientshad2mutationsfound onknown OCA genesor 1XLmutation. • 19(45%)patientshad1previously reported diseasecausing mutationsfound onOCAgenes. • 8(19%)patientshadNOmutationsfoundon albinismgenes. Twomutations • 8(53%)weremolecularlydiagnosedwithtwomutationsin theOCA1gene. • 5(33%)weremolecularlydiagnosedwithtwomutationsin theOCA2gene. • 1(6%)patienthadahemizygousmutationinOA1. • 1(6%)patienthadtwomutationsinHPSgene. 8 Onemutation • • • • 9(47%)patientshadonemutationfound inOCA1 7(37%)patientshadonemutationfound inOCA2 1(5%)patienthadone mutationfound inOCA4 2(11%)patientshad2OCA1variants(Ser192Tyr) Phenotypicfindingsin44patients clinicallydiagnosedwithalbinism • All(100%)patientshave decreaseddistancebestcorrected visualacuitywithlargevariation(20/25-20/300) • All(100%)patientshave fovealdefects • 86%ofpatienthavenystagmus • 80%ofpatientshaveirisTIDs • 68%ofpatientshaveopticnerve anomalies 9 Correlationclinicalscoringwith genetictestingresults • 15patientswith2OCAmutationsor1XLmutationfound ALLhavescoresof4-5 • 19patientswith1OCAmutationfound - rangebetween14.5 • 8patientswithNOmutationfound- rangebetween1.5-4 Correlationphenotypewithgenetic testingresults • Nodifferenceinthedegreeofpigmentationwasnoted betweenthepatientswith2vs.1mutationorinassociation withany particulartype ofalbinism. • Patientswithmildclinicalfeaturesmayalsohave2mutations, whilepatientswithtypicalclinicalfeaturesofalbinismhave justoneornomutationfound. 10 OCA1,2/2 OCA22/2 11 OCA1,1/2 OCA2,1/2 12 Conclusions • Wedidnot findastrongcorrelationbetweenphenotype and genotype inalbinism,however: • Patientswithmorecompleteandtypicalphenotype aremore likelytohavethediseasecausinggeneticmutationsfound on testing. • Asfound, priorOCA1tendstobemorecommonthenthe other genes. • Whencomparingpatientswithaclinicaldiagnosisofalbinism whohave1vs2mutations,wefindthattheaveragevision is betterandtheaverage"albinismscore”islowerforthose withonly onemutation. Conclusions • Genetictestingresultshavetaughtusthatwemustbroaden our clinicaldefinition. • Inthepastonly patientswithcompleteOCAwerediagnosed becauseonlythey mettheCLINICALdiagnosticcriteria. • Patientswithjustone mutationfound haveonaveragebetter visionandalower"albinismscore”.Thismeanseitherthereis a“missing”mutationthatismildORthesepatientshave featuresofalbinismwithadifferentcause. 13 Discussion • Genetictestingisimportantforboth patientsand clinicians becauseunderstandingthepathogenic mutationsoffersmore insightandleadstoamoreaccurateprognosisforthese disorders. • Moleculartestingforpatientsclinicallydiagnosedwith albinismwillhelpdeterminewhichgenesand/ormutations aretheprincipalplayersinthedisorder andthuswhichgenes shouldbeaddressedwhendeveloping futuretherapiesand treatment. Takehomepoints • Moleculargenetictestingisavailableforalbinism. • Somepatientswithonlymildfindingswillhave2diseasecausingmutationsandcanbeaccuratelydiagnosed,avoiding yearsofuncertainty. • SomepatientsmayhaveHPS,apotentiallylifethreatening diagnosis,butmayhavefewbleedingissuesandlook justlike completeOCA. • Testingapanelofalbinismgenesisimportantandoffering moleculargenetictestingtopatientsisimportant. 14 Acknowledgements • Arlene DrackMD • EdStone, MD • Wynn Institute forVision Research Johnny Tran, Wanda Pfeifer, Sajag Bhattari,Andy Kemerley, KaiWang, Zhaoihui Hu Thankyou 15 SecondMidwestPediatric OphthalmologySymposium: FridaySeptember15,2017. UniversityofIowa,IowaCity PediatricOphthalmology&AdultStrabismus ServiceatUniversityofIowa Arlene V. Drack, MD Ronald V. Keech, MD, Associate Professor in Ophthalmic Genetics Director, Pediatric ERG Service Associate Professor of Ophthalmology and Visual Sciences Associate Professor of Pediatrics Pavlina S. Kemp, MD Clinical Assistant Professor of Ophthalmology and Visual Sciences Clinical Assistant Professor of Pediatrics Alina V. Dumitrescu, MD Clinical Assistant Professor of Ophthalmology and Ophthalmic Genetics Clinical Assistant Professor of Pediatrics Scott A. Larson, MD Associate Professor of Ophthalmology and Visual Sciences Richard J. Olson, MD William E. Scott, MD Director, Medical Education, Dept of Ophthalmology Clinical Associate Professor of Ophthalmology and Visual Sciences Clinical Associate Professor of Pediatrics Professor Emeritus of Ophthalmology Pediatric Ophthalmology & Adult Strabismus 16