psychosis genes? next generation genetics in … · next generation genetics in clinical psychiatry...

Psychosisgenes?Nextgenerationgeneticsinclinicalpsychiatry

AnnaCNeedImperialCollegeLondon

Overview

• Aretheregeneticvariantsthatcause*psychosis?• Canwetestforthemintheclinic?• Canweusethisinformationtohelptreatpatients?

Howcoulda‘geneticdiagnosis’beusedtohelppatients?

• Couldidentifyatreatable(curable)illness!• Canhelpguidedrugchoice– seizurethreshold– obesity

• Genetictestingandmonitoringoffamilymembers• Specificeducationalsupportrecommendations• Applicationsforeducationalsupport• Helpunderstandwhy– guil– preventdangerousalternativetreatments

PatientPower

• Patients(ortheirparents)withaspecificgeneticdiagnosiscanconnectthroughsocialmedia– Getbetterprognosis– Supporteachotheremotionally– Sharetreatmentexperiences– Discusssymptoms

• Provideinsightthatclinicianswithlimitedexposuretoverysmallnumbersofcasescannot

Mendelian vs.Complex

AutosomaldominantAutosomalRecessiveX-linkedRecessiveX-linkeddomainant

Mitochondrial

MultiplegeneticcontributorsStrongenvironmentaleffects

Gene-geneinteractionsGene-environmental interactions

MendelianFormsofComplexBrainDisorders

• Alzheimer’s:PSEN1,PSEN2,APP….• Parkinsons:SNCA,Parkin,PINK1...• Epilepsy:LGI1,CHRNA4,KCNQ3...

MendelianFormsofSchizophrenia?

1. CNVsandpsychosis2. Genesandpsychosis3. Mendeliandisordersthat

causepsychosis4. The100,000genomesproject5. Our‘diagnosticsequencing’

pilot

(no)

CopyNumberVariants(CNVs)

(ThankstotheAutismReadingRoom,http://readingroom.mindspec.org/fortheFigure)

22q11:Velo-cardio-facialsyndrome• hypoparathyroidism• Underdevelopedthymusor

absentthymus,whichresultsinproblemsintheimmunesystem

• heartdefects• cleftlipand/orpalate

• Approx 1/3VCFSpatientsdevelopschizophrenia• Approximately1%ofpatientswithschizophreniahave22qDS.• Theschizophreniain22qDSisindistinguishablebysymptoms,treatmentresponse,neurocognitiveprofile,orMRIbrainanomalies.

Grayton etal.,2012doi:10.1016/j.pneurobio.2012.07.005

Similarly…

CNVs

• Clinicalgeneticsservicesscreenentiregenome(allchromosomesatonce)andreportbackpathogenicvariants• Couldbegeneticallydiagnosingseveralpercentofschizophreniacasesalreadywithclinicalgeneticanalysis



pilot

SETD1A(Singhetal.,NatureNeuroscience,March2016)



pilot

MendelianGeneticDisordersandPsychosis

• No“Mendelianschizophrenias”• Manydisorderscanpresentwithpsychosisaspartoftheirsymptoms

Mendelian disordersthatcanmanifestwithpsychosis*

Disorder Gene Symbol Disorder Gene Symbol

ADRENOLEUKODYSTROPHY; ALD ABCD1 USHER SYNDROME, TYPE I; USH1 MYO7AACYL-CoA DEHYDROGENASE,SHORT-CHAIN, DEFICIENCY OF; ACADSD ACADS NORRIE DISEASE; ND NDPSUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY; SSADHD ALDH5A1 NEUROFIBROMATOSIS, TYPE I; NF1 NF1

METACHROMATIC LEUKODYSTROPHY ARSA CEREBRAL ARTERIOPATHYWITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY NOTCH3ARGININOSUCCINIC ACIDURIA ASL NIEMANN-PICK DISEASE, TYPE C1; NPC1 NPC1DYSTONIA 12; DYT12 ATP1A3 NIEMANN-PICK DISEASE, TYPE C2; NPC2 NPC2DARIER-WHITE DISEASE; DAR ATP2A2 ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO OTCWILSON DISEASE ATP7B PHENYLKETONURIA; PKU PAHMACHADO-JOSEPH DISEASE; MJD ATXN3 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1 PANK2MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7 C10orf2 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 9; EIEE9 PCDH19FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS; FTDALS C9orf72 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 2; PPNAD2 PDE11AMIGRAINE, FAMILIAL HEMIPLEGIC,WITH CEREBELLAR ATAXIA CACNA1A BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 5; IBGC5 PDGFBHOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY CBS SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS; SANDO POLGCEROID LIPOFUSCINOSIS, NEURONAL, 3; CLN3 CLN3 PORPHYRIA VARIEGATA PPOXCEROID LIPOFUSCINOSIS, NEURONAL, 4A, AUTOSOMAL RECESSIVE; CLN4A CLN6 SPINOCEREBELLAR ATAXIA 12; SCA12 PPP2R2BCOPROPORPHYRIA, HEREDITARY; HCP CPOX PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1; PPNAD1 PRKAR1ACEREBROTENDINOUS XANTHOMATOSIS; CTX CYP27A1 HUNTINGTON DISEASE-LIKE 1; HDL1 PRNPWOODHOUSE-SAKATI SYNDROME DCAF17 PRION DISEASE PRNPPARKINSON DISEASE 7, AUTOSOMAL RECESSIVE, EARLY-ONSET; PARK7 DJ1 / PARK7 ALZHEIMER DISEASE 3 PSEN1CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B DNAJC5 ALZHEIMER DISEASE 4 PSEN2CEREBELLAR ATAXIA, DEAFNESS, AND NARCOLEPSY, AUTOSOMAL DOMINANT; ADCADN DNMT1 COFFIN-LOWRY SYNDROME;CLS RPS6KA3LIPOID PROTEINOSIS OF URBACH AND WIETHE ECM1 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN SLC12A6KLEEFSTRA SYNDROME EHMT1 BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1; IBGC1 SLC20A2FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATED GRN CITRULLINEMIA, TYPE II, ADULT-ONSET; CTLN2 SLC25A13USHER SYNDROME, TYPE IIIB; USH3B HARS HARTNUP DISORDER SLC6A19NARCOLEPSY 1; NRCLP1 HCRT CEREBRAL CREATINE DEFICIENCY SYNDROME 1 SLC6A8TAY-SACHS DISEASE; TSD HEXA LYSINURIC PROTEIN INTOLERANCE; LPI SLC7A7SANDHOFF DISEASE HEXB PARKINSON DISEASE 1, AUTOSOMAL DOMINANT; PARK1/ PARKINSON DISEAE 4 SNCAACUTE PORPHYRIA INTERMITTENT HMBS SPINOCEREBELLAR ATAXIA 17; SCA17 TBPMENTAL RETARDATION, X-LINKED,SYNDROMIC 10; MRXS10 HSD17B10 VELOCARDIOFACIAL SYNDROME TBX1HUNTINGTON DISEASE; HD HTT THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT; GRTH THRBHURLER-SCHEIE SYNDROME IDUA MOHR-TRANEBJAERG SYNDROME; MTS TIMM8ACEREBRAL AMYLOID ANGIOPATHY, ITM2B-RELATED, 2 ITM2B TUBEROUS SCLEROSIS 1; TSC1 TSC1EPILEPSY, NOCTURNAL FRONTAL LOBE, 5; ENFL5 KCNT1 MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 2; MC3DN2 TTC19EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1 LGI1 AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED TTRLUBS X-LINKED MENTAL RETARDATION SYNDROME; MRXSL MECP2 CHOREOACANTHOCYTOSIS; CHAC VPS13AMENTAL RETARDATION, X-LINKED, SYNDROME 13; MRXS13 MECP2 WOLFRAM SYNDROME 1; WFS1 WFS1LUJAN-FRYNS SYNDROME MED12 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT; WFSL WFS1METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE MMACHC MCLEOD SYNDROME; MCLDS XK

SPASTIC PARAPLEGIA 15,AUTOSOMAL RECESSIVE;SPG15 ZFYVE26

*SearchedOMIMphenotypedescriptionsfor“psycho*”,“hallucinations”,“delusions”,“parano*”,“mania”and“psychiatric”andcuratedusingclinicalreportsinPubMed.

Mendelian disordersthatcanmanifestwithpsychosis*

Disorder Gene Symbol Disorder Gene Symbol

ADRENOLEUKODYSTROPHY; ALD ABCD1 USHER SYNDROME, TYPE I; USH1 MYO7AACYL-CoA DEHYDROGENASE,SHORT-CHAIN, DEFICIENCY OF; ACADSD ACADS NORRIE DISEASE; ND NDPSUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY; SSADHD ALDH5A1 NEUROFIBROMATOSIS, TYPE I; NF1 NF1

METACHROMATIC LEUKODYSTROPHY ARSA CEREBRAL ARTERIOPATHYWITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY NOTCH3ARGININOSUCCINIC ACIDURIA ASL NIEMANN-PICK DISEASE, TYPE C1; NPC1 NPC1DYSTONIA 12; DYT12 ATP1A3 NIEMANN-PICK DISEASE, TYPE C2; NPC2 NPC2DARIER-WHITE DISEASE; DAR ATP2A2 ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO OTCWILSON DISEASE ATP7B PHENYLKETONURIA; PKU PAHMACHADO-JOSEPH DISEASE; MJD ATXN3 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1 PANK2MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7 C10orf2 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 9; EIEE9 PCDH19FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS; FTDALS C9orf72 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 2; PPNAD2 PDE11AMIGRAINE, FAMILIAL HEMIPLEGIC,WITH CEREBELLAR ATAXIA CACNA1A BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 5; IBGC5 PDGFBHOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY CBS SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS; SANDO POLGCEROID LIPOFUSCINOSIS, NEURONAL, 3; CLN3 CLN3 PORPHYRIA VARIEGATA PPOXCEROID LIPOFUSCINOSIS, NEURONAL, 4A, AUTOSOMAL RECESSIVE; CLN4A CLN6 SPINOCEREBELLAR ATAXIA 12; SCA12 PPP2R2BCOPROPORPHYRIA, HEREDITARY; HCP CPOX PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1; PPNAD1 PRKAR1ACEREBROTENDINOUS XANTHOMATOSIS; CTX CYP27A1 HUNTINGTON DISEASE-LIKE 1; HDL1 PRNPWOODHOUSE-SAKATI SYNDROME DCAF17 PRION DISEASE PRNPPARKINSON DISEASE 7, AUTOSOMAL RECESSIVE, EARLY-ONSET; PARK7 DJ1 / PARK7 ALZHEIMER DISEASE 3 PSEN1CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B DNAJC5 ALZHEIMER DISEASE 4 PSEN2CEREBELLAR ATAXIA, DEAFNESS, AND NARCOLEPSY, AUTOSOMAL DOMINANT; ADCADN DNMT1 COFFIN-LOWRY SYNDROME;CLS RPS6KA3LIPOID PROTEINOSIS OF URBACH AND WIETHE ECM1 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN SLC12A6KLEEFSTRA SYNDROME EHMT1 BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1; IBGC1 SLC20A2FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATED GRN CITRULLINEMIA, TYPE II, ADULT-ONSET; CTLN2 SLC25A13USHER SYNDROME, TYPE IIIB; USH3B HARS HARTNUP DISORDER SLC6A19NARCOLEPSY 1; NRCLP1 HCRT CEREBRAL CREATINE DEFICIENCY SYNDROME 1 SLC6A8TAY-SACHS DISEASE; TSD HEXA LYSINURIC PROTEIN INTOLERANCE; LPI SLC7A7SANDHOFF DISEASE HEXB PARKINSON DISEASE 1, AUTOSOMAL DOMINANT; PARK1/ PARKINSON DISEAE 4 SNCAACUTE PORPHYRIA INTERMITTENT HMBS SPINOCEREBELLAR ATAXIA 17; SCA17 TBPMENTAL RETARDATION, X-LINKED,SYNDROMIC 10; MRXS10 HSD17B10 VELOCARDIOFACIAL SYNDROME TBX1HUNTINGTON DISEASE; HD HTT THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT; GRTH THRBHURLER-SCHEIE SYNDROME IDUA MOHR-TRANEBJAERG SYNDROME; MTS TIMM8ACEREBRAL AMYLOID ANGIOPATHY, ITM2B-RELATED, 2 ITM2B TUBEROUS SCLEROSIS 1; TSC1 TSC1EPILEPSY, NOCTURNAL FRONTAL LOBE, 5; ENFL5 KCNT1 MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 2; MC3DN2 TTC19EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1 LGI1 AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED TTRLUBS X-LINKED MENTAL RETARDATION SYNDROME; MRXSL MECP2 CHOREOACANTHOCYTOSIS; CHAC VPS13AMENTAL RETARDATION, X-LINKED, SYNDROME 13; MRXS13 MECP2 WOLFRAM SYNDROME 1; WFS1 WFS1LUJAN-FRYNS SYNDROME MED12 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT; WFSL WFS1METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE MMACHC MCLEOD SYNDROME; MCLDS XK

SPASTIC PARAPLEGIA 15,AUTOSOMAL RECESSIVE;SPG15 ZFYVE26

*SearchedOMIMphenotypedescriptionsfor“psycho*”,“hallucinations”,“delusions”,“parano*”,“mania”and“psychiatric”andcuratedusingclinicalreportsinPubMed.

Darier-WhiteDisease(OMIM):“Darier-Whitedisease,alsoknownaskeratosisfollicularis,isanautosomaldominantskindisordercharacterizedbywartypapulesandplaquesinseborrheic areas(centraltrunk,flexures,scalp,andforehead),palmoplantar pits,anddistinctivenailabnormalities(Sakuntabhaietal.,1999).…mentalillnesses,suchaspsychosisandaffectivedisorder,havebeenreportedinassociationwithDarier disease.”

Wolframsyndrome(OMIM):“Wolframsyndrome-1isarareandsevereautosomalrecessiveneurodegenerativediseasecharacterizedbydiabetesmellitus,opticatrophy,diabetesinsipidus,anddeafness(DIDMOAD).Additionalclinicalfeaturesmayincluderenalabnormalities,ataxia,dementiaormentalretardation,anddiversepsychiatricillnesses.”Acuteintermittentporphyria(OMIM):”Acuteepisodesofavarietyofgastrointestinalandneuropathicsymptoms;betweenepisodes,thepatientishealthy.Abdominalpainisthemostcommonsymptom,sometimeswithconstipationandurinaryretention;paraesthesias andparalysisalsooccur,anddeathmayresultfromrespiratoryparalysis.Manyotherphenomena,includingseizures,psychoticepisodes,andhypertension,mayoccurinacuteattacks”

“Iwouldknowifmypatienthadthat!”(Variablepenetrance/expressivity)

• ‘Genome-first’approachhasshownthat,likeCNVs,Mendeliandisordersmuchmorevariablethanpreviouslythought

• Maypresentwithsubsetofclassicsymptoms(orentirelynewsymptoms)

• Somemaypresentwithjustpsychosis!

Canwediagnosethesenow?

• No– toomanygenes– presentationtoounpredictable

• Needtobeabletolookatallcandidatesatonce– genome/exomeseq

1. CNVsandpsychosis2. Developmentaldisordersand

psychosis3. Mendeliandisordersthatcause

psychosis4. The100,000genomesproject5. Our‘diagnosticsequencing’pilot

The100,000GenomesProject

Comingsoon….schizophrenia?

FundedbyHEEtotrainNHSStafftoleadtheintegrationofgenomictechnologyintopatientcarewithintheNHS

Moregeneticforms?

–Childhoodonsetpsychosis–Multiplexfamilies–Patientswithcomorbidities– Treatmentresistantschizophrenia

1. CNVsandpsychosis2. Developmentaldisordersand

psychosis3. Mendeliandisordersthatcause

psychosis4. The100,000genomesproject5. Our‘diagnosticsequencing’pilot

GeneticResearchintoChildhoodOnsetPsychosis

Dr.AnthonyJames

• Recruitingpatientsdiagnosedwithpsychoticillnessbeforeage14 [email protected]

Incollaborationwith…PrimaryObjectiveTodetermineifnextgenerationsequencingcanleadtoclinicallyrelevantgeneticdiagnosisinchildpsychiatry.

SecondaryObjective1.Toidentifycandidategenesthatarerelevanttothemorecommonadultonsetformsofthedisorder.2.Toestablishadatabaseofpatientswithchildhoodonsetpsychosisandtheirfamilymembersthatarewillingtobecontactedaboutotherstudiesthatwillhelpustounderstandtheetiology,expressionandcourseofchildhoodonsetpsychosis.

ACTIVELYRECRUITING!Aimingfor100,have27…

• SouthLondonandMaudsley• SouthWestLondonandSt

George's• Leeds&YorkPartnership• LincolnshirePartnership• Northumberland,Tyne&Wear• MerseyCare• Bradford• OxfordHealth• CornwallFoundationTrust• CentralandNorthWestLondon• GOSH WhittingtonHospital

• BarnetEnfieldandHaringey• CentralManchesterUniversity

Hospitals• BirminghamChildrens Hospital• LancashireCare• DorsetHealthcare• SouthWestYorkshirePartnership• NHSFoundationTrust• Tees,Esk andWear• LeicestershirePartnership• Rotherham,Doncaster andSouth

Humber• Northamptonshire

Interesting?

• Sleepdisorders

• Twohavesiblingswhohaveundergonegenderreassignment

Conclusions

• Aretheregeneticvariantsthatcause psychosis?– Yes,therearelikelytobehundreds(atleast)

• Canwetestforthemintheclinic?– CNVscanbeidentifiedwithexistinggeneticsservices– Sequencevariantssoon…

• Canweusethisinformationtohelptreatpatients?– I’lltellyounextyear!

AcknowledgementsTonyJamesClareBorsayMitra AmeriAmyClaringboldClaudiaAdele

Marinos KyriakopoulosKouser ShaikJosephHorneFionaPadgettIsabelEllorySarojit GangulyGillianRoseJonGoldin

Navin ChandraBiki ValleJaneWhittakerRuthMarshallAlisonRobinsonAshleyliewBiradar RajeevCatehrine O’CallaghanNiloufar MirhaghaniJoseMediavillaAbhay RathoreNicoletta GentiliDebbieMarsdenRichardChurch

MarieCurieCareerIntegrationGrant;ElsieWiddowson Fellowship

Doyouknowofsomeonediagnosedwithpsychosisbeforeage14?

- Pleaseemailme:[email protected]

- orTonyJames:[email protected]

Itwillbeveryminimumtroubletoyou!

psychosis genes? next generation genetics in … · next generation genetics in clinical psychiatry...

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