Psychosis genes? Next generation genetics in clinical psychiatry. Anna C Need Imperial College London

Transcription

1 Psychosis genes? Next generation genetics in clinical psychiatry Anna C Need Imperial College London

2 Overview Are there genetic variants that cause* psychosis? Can we test for them in the clinic? Can we use this information to help treat patients?

3 How could a genetic diagnosis be used to help patients? Could identify a treatable (curable) illness! Can help guide drug choice seizure threshold obesity Genetic testing and monitoring of family members Specific educational support recommendations Applications for educational support Help understand why guil prevent dangerous alternative treatments

4 Patient Power Patients (or their parents) with a specific genetic diagnosis can connect through social media Get better prognosis Support each other emotionally Share treatment experiences Discuss symptoms Provide insight that clinicians with limited exposure to very small numbers of cases cannot

5 Mendelian vs. Complex Autosomal dominant Autosomal Recessive X-linked Recessive X-linked domainant Mitochondrial Multiple genetic contributors Strong environmental effects Gene-gene interactions Gene-environmental interactions

6 Mendelian Forms of Complex Brain Disorders Alzheimer s: PSEN1, PSEN2, APP. Parkinsons: SNCA, Parkin, PINK1... Epilepsy: LGI1, CHRNA4, KCNQ3...

7 Mendelian Forms of Schizophrenia? (no) 1. CNVs and psychosis 2. Genes and psychosis 3. Mendelian disorders that cause psychosis 4. The 100,000 genomes project 5. Our diagnostic sequencing pilot

8 Copy Number Variants (CNVs) (Thanks to the Autism Reading Room, the Figure)

9 22q11: Velo-cardio-facial syndrome hypoparathyroidism Underdeveloped thymus or absent thymus, which results in problems in the immune system heart defects cleft lip and/or palate Approx 1/3 VCFS patients develop schizophrenia Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS is indistinguishable by symptoms, treatment response, neurocognitive profile, or MRI brain anomalies.

10 Similarly Grayton et al., 2012 doi: /j.pneurobio

11 CNVs Clinical genetics services screen entire genome (all chromosomes at once) and report back pathogenic variants Could be genetically diagnosing several percent of schizophrenia cases already with clinical genetic analysis

12 1. CNVs and psychosis 2. Genes and psychosis 3. Mendelian disorders that cause psychosis 4. The 100,000 genomes project 5. Our diagnostic sequencing pilot

13 SETD1A (Singh et al., Nature Neuroscience, March 2016)

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16 1. CNVs and psychosis 2. Genes and psychosis 3. Mendelian disorders that cause psychosis 4. The 100,000 genomes project 5. Our diagnostic sequencing pilot

17 Mendelian Genetic Disorders and Psychosis No Mendelian schizophrenias Many disorders can present with psychosis as part of their symptoms

18 Mendelian disorders that can manifest with psychosis* Disorder Gene Symbol Disorder ADRENOLEUKODYSTROPHY; ALD ABCD1 USHER SYNDROME, TYPE I; USH1 MYO7A ACYL-CoA DEHYDROGENASE,SHORT-CHAIN, DEFICIENCY OF; ACADSD ACADS NORRIE DISEASE; ND NDP SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY; SSADHD ALDH5A1 NEUROFIBROMATOSIS, TYPE I; NF1 NF1 METACHROMATIC LEUKODYSTROPHY ARSA CEREBRAL ARTERIOPATHYWITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY NOTCH3 ARGININOSUCCINIC ACIDURIA ASL NIEMANN-PICK DISEASE, TYPE C1; NPC1 NPC1 DYSTONIA 12; DYT12 ATP1A3 NIEMANN-PICK DISEASE, TYPE C2; NPC2 NPC2 DARIER-WHITE DISEASE; DAR ATP2A2 ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO OTC WILSON DISEASE ATP7B PHENYLKETONURIA; PKU PAH MACHADO-JOSEPH DISEASE; MJD ATXN3 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1 PANK2 MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7 C10orf2 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 9; EIEE9 PCDH19 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS; FTDALS C9orf72 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 2; PPNAD2 PDE11A MIGRAINE, FAMILIAL HEMIPLEGIC,WITH CEREBELLAR ATAXIA CACNA1A BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 5; IBGC5 PDGFB HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY CBS SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS; SANDO POLG CEROID LIPOFUSCINOSIS, NEURONAL, 3; CLN3 CLN3 PORPHYRIA VARIEGATA PPOX CEROID LIPOFUSCINOSIS, NEURONAL, 4A, AUTOSOMAL RECESSIVE; CLN4A CLN6 SPINOCEREBELLAR ATAXIA 12; SCA12 PPP2R2B COPROPORPHYRIA, HEREDITARY; HCP CPOX PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1; PPNAD1 PRKAR1A CEREBROTENDINOUS XANTHOMATOSIS; CTX CYP27A1 HUNTINGTON DISEASE-LIKE 1; HDL1 PRNP WOODHOUSE-SAKATI SYNDROME DCAF17 PRION DISEASE PRNP PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE, EARLY-ONSET; PARK7 DJ1 / PARK7 ALZHEIMER DISEASE 3 PSEN1 CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B DNAJC5 ALZHEIMER DISEASE 4 PSEN2 CEREBELLAR ATAXIA, DEAFNESS, AND NARCOLEPSY, AUTOSOMAL DOMINANT; ADCADN DNMT1 COFFIN-LOWRY SYNDROME;CLS RPS6KA3 LIPOID PROTEINOSIS OF URBACH AND WIETHE ECM1 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN SLC12A6 KLEEFSTRA SYNDROME EHMT1 BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1; IBGC1 SLC20A2 FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATED GRN CITRULLINEMIA, TYPE II, ADULT-ONSET; CTLN2 SLC25A13 USHER SYNDROME, TYPE IIIB; USH3B HARS HARTNUP DISORDER SLC6A19 NARCOLEPSY 1; NRCLP1 HCRT CEREBRAL CREATINE DEFICIENCY SYNDROME 1 SLC6A8 TAY-SACHS DISEASE; TSD HEXA LYSINURIC PROTEIN INTOLERANCE; LPI SLC7A7 SANDHOFF DISEASE HEXB PARKINSON DISEASE 1, AUTOSOMAL DOMINANT; PARK1/ PARKINSON DISEAE 4 SNCA ACUTE PORPHYRIA INTERMITTENT HMBS SPINOCEREBELLAR ATAXIA 17; SCA17 TBP MENTAL RETARDATION, X-LINKED,SYNDROMIC 10; MRXS10 HSD17B10 VELOCARDIOFACIAL SYNDROME TBX1 HUNTINGTON DISEASE; HD HTT THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT; GRTH THRB HURLER-SCHEIE SYNDROME IDUA MOHR-TRANEBJAERG SYNDROME; MTS TIMM8A CEREBRAL AMYLOID ANGIOPATHY, ITM2B-RELATED, 2 ITM2B TUBEROUS SCLEROSIS 1; TSC1 TSC1 EPILEPSY, NOCTURNAL FRONTAL LOBE, 5; ENFL5 KCNT1 MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 2; MC3DN2 TTC19 EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1 LGI1 AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED TTR LUBS X-LINKED MENTAL RETARDATION SYNDROME; MRXSL MECP2 CHOREOACANTHOCYTOSIS; CHAC VPS13A MENTAL RETARDATION, X-LINKED, SYNDROME 13; MRXS13 MECP2 WOLFRAM SYNDROME 1; WFS1 WFS1 LUJAN-FRYNS SYNDROME MED12 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT; WFSL WFS1 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblc TYPE MMACHC MCLEOD SYNDROME; MCLDS XK SPASTIC PARAPLEGIA 15,AUTOSOMAL RECESSIVE;SPG15 *Searched OMIM phenotype descriptions for psycho*, hallucinations, delusions, parano*, mania and psychiatric and curated using clinical reports in PubMed. Gene Symbol ZFYVE26

19 Mendelian disorders that can manifest with psychosis* Darier-White Disease (OMIM): Darier-White disease, also known as keratosis follicularis, is an autosomal dominant skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp, and forehead), palmoplantar pits, and distinctive nail abnormalities (Sakuntabhai et al., 1999). mental illnesses, such as psychosis and affective disorder, have been reported in association with Darier disease. Disorder Gene Symbol Disorder ADRENOLEUKODYSTROPHY; ALD ABCD1 USHER SYNDROME, TYPE I; USH1 MYO7A ACYL-CoA DEHYDROGENASE,SHORT-CHAIN, DEFICIENCY OF; ACADSD ACADS NORRIE DISEASE; ND NDP SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY; SSADHD ALDH5A1 NEUROFIBROMATOSIS, TYPE I; NF1 NF1 METACHROMATIC LEUKODYSTROPHY ARSA CEREBRAL ARTERIOPATHYWITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY NOTCH3 ARGININOSUCCINIC ACIDURIA ASL NIEMANN-PICK DISEASE, TYPE C1; NPC1 NPC1 DYSTONIA 12; DYT12 ATP1A3 NIEMANN-PICK DISEASE, TYPE C2; NPC2 NPC2 DARIER-WHITE DISEASE; DAR ATP2A2 ORNITHINE TRANSCARBAMYLASE DEFICIENCY, HYPERAMMONEMIA DUE TO OTC WILSON DISEASE ATP7B PHENYLKETONURIA; PKU PAH MACHADO-JOSEPH DISEASE; MJD ATXN3 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 1; NBIA1 PANK2 MITOCHONDRIAL DNA DEPLETION SYNDROME 7 (HEPATOCEREBRAL TYPE); MTDPS7 C10orf2 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 9; EIEE9 PCDH19 FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS; FTDALS C9orf72 PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 2; PPNAD2 PDE11A MIGRAINE, FAMILIAL HEMIPLEGIC,WITH CEREBELLAR ATAXIA CACNA1A BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 5; IBGC5 PDGFB HOMOCYSTINURIA DUE TO CYSTATHIONINE BETA-SYNTHASE DEFICIENCY CBS SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS; SANDO POLG Wolfram syndrome(omim): Wolfram syndrome-1 is a rare and severe autosomal recessive neurodegenerative disease characterized by diabetes mellitus, optic atrophy, diabetes insipidus, and deafness (DIDMOAD). Additional clinical features may include renal abnormalities, ataxia, dementia or mental retardation, and diverse psychiatric illnesses. CEROID LIPOFUSCINOSIS, NEURONAL, 3; CLN3 CLN3 PORPHYRIA VARIEGATA PPOX CEROID LIPOFUSCINOSIS, NEURONAL, 4A, AUTOSOMAL RECESSIVE; CLN4A CLN6 SPINOCEREBELLAR ATAXIA 12; SCA12 PPP2R2B COPROPORPHYRIA, HEREDITARY; HCP CPOX PIGMENTED NODULAR ADRENOCORTICAL DISEASE, PRIMARY, 1; PPNAD1 PRKAR1A CEREBROTENDINOUS XANTHOMATOSIS; CTX CYP27A1 HUNTINGTON DISEASE-LIKE 1; HDL1 PRNP WOODHOUSE-SAKATI SYNDROME DCAF17 PRION DISEASE PRNP PARKINSON DISEASE 7, AUTOSOMAL RECESSIVE, EARLY-ONSET; PARK7 DJ1 / PARK7 ALZHEIMER DISEASE 3 PSEN1 CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B DNAJC5 ALZHEIMER DISEASE 4 PSEN2 CEREBELLAR ATAXIA, DEAFNESS, AND NARCOLEPSY, AUTOSOMAL DOMINANT; ADCADN DNMT1 COFFIN-LOWRY SYNDROME;CLS RPS6KA3 LIPOID PROTEINOSIS OF URBACH AND WIETHE ECM1 AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY; ACCPN SLC12A6 KLEEFSTRA SYNDROME EHMT1 BASAL GANGLIA CALCIFICATION, IDIOPATHIC, 1; IBGC1 SLC20A2 FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, GRN-RELATED GRN CITRULLINEMIA, TYPE II, ADULT-ONSET; CTLN2 SLC25A13 USHER SYNDROME, TYPE IIIB; USH3B HARS HARTNUP DISORDER SLC6A19 Acute intermittent porphyria(omim): Acute episodes of a variety of gastrointestinal and neuropathic symptoms; between episodes, the patient is healthy. Abdominal pain is the most common symptom, sometimes with constipation and urinary retention; paraesthesias and paralysis also occur, and death may result from respiratory paralysis. Many other phenomena, including seizures, psychotic episodes, and hypertension, may occur in acute attacks NARCOLEPSY 1; NRCLP1 HCRT CEREBRAL CREATINE DEFICIENCY SYNDROME 1 SLC6A8 TAY-SACHS DISEASE; TSD HEXA LYSINURIC PROTEIN INTOLERANCE; LPI SLC7A7 SANDHOFF DISEASE HEXB PARKINSON DISEASE 1, AUTOSOMAL DOMINANT; PARK1/ PARKINSON DISEAE 4 SNCA ACUTE PORPHYRIA INTERMITTENT HMBS SPINOCEREBELLAR ATAXIA 17; SCA17 TBP MENTAL RETARDATION, X-LINKED,SYNDROMIC 10; MRXS10 HSD17B10 VELOCARDIOFACIAL SYNDROME TBX1 HUNTINGTON DISEASE; HD HTT THYROID HORMONE RESISTANCE, GENERALIZED, AUTOSOMAL DOMINANT; GRTH THRB HURLER-SCHEIE SYNDROME IDUA MOHR-TRANEBJAERG SYNDROME; MTS TIMM8A CEREBRAL AMYLOID ANGIOPATHY, ITM2B-RELATED, 2 ITM2B TUBEROUS SCLEROSIS 1; TSC1 TSC1 EPILEPSY, NOCTURNAL FRONTAL LOBE, 5; ENFL5 KCNT1 MITOCHONDRIAL COMPLEX III DEFICIENCY, NUCLEAR TYPE 2; MC3DN2 TTC19 EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1 LGI1 AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED TTR LUBS X-LINKED MENTAL RETARDATION SYNDROME; MRXSL MECP2 CHOREOACANTHOCYTOSIS; CHAC VPS13A MENTAL RETARDATION, X-LINKED, SYNDROME 13; MRXS13 MECP2 WOLFRAM SYNDROME 1; WFS1 WFS1 LUJAN-FRYNS SYNDROME MED12 WOLFRAM-LIKE SYNDROME, AUTOSOMAL DOMINANT; WFSL WFS1 METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblc TYPE MMACHC MCLEOD SYNDROME; MCLDS XK SPASTIC PARAPLEGIA 15,AUTOSOMAL RECESSIVE;SPG15 *Searched OMIM phenotype descriptions for psycho*, hallucinations, delusions, parano*, mania and psychiatric and curated using clinical reports in PubMed. Gene Symbol ZFYVE26

20 I would know if my patient had that! (Variable penetrance/ expressivity) Genome-first approach has shown that, like CNVs, Mendelian disorders much more variable than previously thought May present with subset of classic symptoms (or entirely new symptoms) Some may present with just psychosis!

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25 Can we diagnose these now? No too many genes presentation too unpredictable Need to be able to look at all candidates at once genome/exome seq

26 1. CNVs and psychosis 2. Developmental disorders and psychosis 3. Mendelian disorders that cause psychosis 4. The 100,000 genomes project 5. Our diagnostic sequencing pilot

27 The 100,000 Genomes Project Funded by HEE to train NHS Staff to lead the integration of genomic technology into patient care within the NHS Coming soon.schizophrenia?

28 More genetic forms? Childhood onset psychosis Multiplex families Patients with comorbidities Treatment resistant schizophrenia

29 1. CNVs and psychosis 2. Developmental disorders and psychosis 3. Mendelian disorders that cause psychosis 4. The 100,000 genomes project 5. Our diagnostic sequencing pilot

30 Genetic Research into Childhood In collaboration with Onset Psychosis Primary Objective To determine if next generation sequencing can lead to clinically relevant genetic diagnosis in child psychiatry. Secondary Objective 1. To identify candidate genes that are relevant to the more common adult onset forms of the disorder. 2. To establish a database of patients with childhood onset psychosis and their family members that are willing to be contacted about other studies that will help us to understand the etiology, expression and course of childhood onset psychosis. Dr. Anthony James Recruiting patients diagnosed with psychotic illness before age 14 a.need@imperial.ac.uk

31 ACTIVELY RECRUITING! Aiming for 100, have 27 South London and Maudsley South West London and St George's Leeds & York Partnership Lincolnshire Partnership Northumberland, Tyne & Wear Mersey Care Bradford Oxford Health Cornwall Foundation Trust Central and North West London GOSH Whittington Hospital Barnet Enfield and Haringey Central Manchester University Hospitals Birmingham Childrens Hospital Lancashire Care Dorset Healthcare South West Yorkshire Partnership NHS Foundation Trust Tees, Esk and Wear Leicestershire Partnership Rotherham, Doncaster and South Humber Northamptonshire

32 Interesting? Sleep disorders Two have siblings who have undergone gender reassignment

33 Conclusions Are there genetic variants that cause psychosis? Yes, there are likely to be hundreds (at least) Can we test for them in the clinic? CNVs can be identified with existing genetics services Sequence variants soon Can we use this information to help treat patients? I ll tell you next year!

34 Acknowledgements Tony James Clare Borsay Mitra Ameri Amy Claringbold Claudia Adele Marinos Kyriakopoulos Kouser Shaik Joseph Horne Fiona Padgett Isabel Ellory Sarojit Ganguly Gillian Rose Jon Goldin Navin Chandra Biki Valle Jane Whittaker Ruth Marshall Alison Robinson Ashley liew Biradar Rajeev Catehrine O Callaghan Niloufar Mirhaghani Jose Mediavilla Abhay Rathore Nicoletta Gentili Debbie Marsden Richard Church Marie Curie Career Integration Grant; Elsie Widdowson Fellowship

35 Do you know of someone diagnosed with psychosis before age 14? - Please me: a.need@imperial.ac.uk - or Tony James: anthony.james@psych.ox.ac.uk It will be very minimum trouble to you!