Download Genotype-Phenotype Correlation in Patients with Albinism

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
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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
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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.
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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.
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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
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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.
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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
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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.
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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
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Correlationclinicalscoringwith
genetictestingresults
• 15patientswith2OCAmutationsor1XLmutationfound ALLhavescoresof4-5
• 19patientswith1OCAmutationfound - rangebetween14.5
• 8patientswithNOmutationfound- rangebetween1.5-4
Correlationphenotypewithgenetic
testingresults
• Nodifferenceinthedegreeofpigmentationwasnoted
betweenthepatientswith2vs.1mutationorinassociation
withany particulartype ofalbinism.
• Patientswithmildclinicalfeaturesmayalsohave2mutations,
whilepatientswithtypicalclinicalfeaturesofalbinismhave
justoneornomutationfound.
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OCA1,2/2
OCA22/2
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OCA1,1/2
OCA2,1/2
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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.
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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.
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Acknowledgements
• Arlene DrackMD
• EdStone, MD
• Wynn Institute forVision Research
Johnny Tran, Wanda Pfeifer, Sajag Bhattari,Andy
Kemerley, KaiWang, Zhaoihui Hu
Thankyou
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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
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