The genome and the metabolome: complementary tools towards diagnosis
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1 The genome and the metabolome: complementary tools towards diagnosis NGS course: Genomic resequencing in medical diagnostics oktober 2014, Rotterdam Prof. dr. Ron Wevers, Department of Laboratory Medicine, Radboudumc, Nijmegen, The Netherlands
2 Targeted metabolomics Organic acids Amino acids Purines Untargeted metabolomics NMR spectroscopy LC-Qtof mass spectrometry
3 Molecular complexity in Life Science Number of Dynamic molecular entities range Genomics Proteomics Metabolomics Typical eukaryotic organisms contain between 4000 and metabolites (Kegg: 16896; HMDB 2012: 7900; HMDB 3.6: 41808)
4 Metabolomics - analysis of all metabolites Uw wereld verandert ook 10,480 features Human plasma, CSF (urine) Controls vs. patient Agilent QTOF MS-data - Reverse phase liquid chromatography - Positive and negative mode - Features Accurate mass ( ) Retention time Intensity XCMS Alignment Peak comparison > 10,000 Features (New) biomarkers for diseases
5 Q-tof mass spectrometry Molecular mass: C 4 H 6 O 4 Methylmalonic acid
6 Accuracy of Q-tof analysis Deviation from actual mass for 19 metabolites (Mass range Dalton) mass number of metabolites
7 Q-tof sensitivity Pipecolic acid added to urine (diluted 50x) Pipecolic acid 500 nmol/l Sensitivity S/N=20 50 nmol/l 5 nmol/l no addition Q-TOF low nanomolar range NMR low micromolar range Factor 1000 more sensitive than NMR!
8 Which features are the IEM biomarkers Experiment Data Preprocessing & Pretreatment Raw data Alignment Peak Comparison Data analyses Corrected t-test Intensity/P Ranking 10,480 features Data interpretation Identification T20 Verification
9 PKU: Patiënt 7 two biomarkers sg st Feature Patient 7 Feature Intensity P-value Mass Ret E E E E E E E E E E E E E E E E E E E E E E E E E E E E Feature 1909 PKU P7 P7 Controls HMDB: phenylalanine PKU Feature 1137 P7 P7 Controls HMDB: glutamylphenylalanine
10 Plasma biomarkers for PKU patients PKU1 66 PKU2 195 PKU7 80 PKU features (7 metabolites) - Phenylalanine - Glutamylphenylalanine - Phenylalanine + C 6 H 10 O 5 - Mass Unknown - Prolyl-L-phenylalanine + H 2 - N-Acetyl-L-phenylalanine - Mass Unknown PKU5 197 PKU4 90 PKU3 73
11 Untargeted metabolomics: Xanthinuria Child, 2.5 months with kidney stones; urine metabolome analysis Xanthine Uric acid CONCLUSIONS: Xanthinuria I (isolated xanthine oxidase) Xanthinuria II (combined xanthine oxidase + aldehyde oxidase defect) Xanthine Uric acid Xanthine oxidase
12 The clinical validation Diagnosis on plasma samples Amino acid disorders Fatty acid oxidation Organic acidurias Miscellaneous PKU MCAD MSUD Xanthinuria II Hyperprolinemia II VLCAD HMG-CoA lyase Amino acylase I Hyperlysinemia MCC Antiquitin (ATQ) def. MAT I/III IVA Beta-ketothiolase Alcaptonuria Dimethylglycinuria Ureidopropionase Current status: 23 inborn errors
13
14 WES and NGMS are complementary Together they contribute to the diagnosis 2012 Patient Targeted Metabolic screen Targeted gene analysis Diagnosis + follow-up 2013 / 2014 Patient Whole exome sequencing Next generation metabolic screening Targeted confirmatory metabolite + enzyme testing Diagnosis + follow-up
15 Kegg database de metabole genen
16 Kegg bevat eiwit en gen indentifiers Tyrosine Hydroxylase
17 The bridge between the exome and the metabolome The Nijmegen approach Nijmegen four day march
18 1. One mutation in a metabolic gene c.1190 A>T p.gly 397Val in GCDH gene; prediction-pathogenic GCDH gene associated with movement disorder/glutaric aciduria Patient has dystonia Did we miss a second mutation (no full coverage in WES)? Organic acid screen Carnitine-ester profile No glutaric aciduria but aminoacylase deficiency 2 Mutations in ACY1 found OMIM
19 The next step DNA metabolome 1 or 2 nucleotide changes of uncertain significance in a metabolic gene: is there supporting info from the metabolome? Metabolome WES Suggestive changes in metabolome or glycome: please check X, Y and Z Integrating software The coding data of the human genes The next step 10,480
20 WES and NGMS in concert
21 PGM1-CDG PMM2-CDG COG7-CDG ALG6-CDG CDG-Congenital Disorders of Glycosylation Glycomics MAN1B1-CDG ATP6V0A2-CDG
22 Whole serum glycomics on nanochip-qtof PNGaseF release of total serum glycans ~24 h preparation time Direct analysis B4GalT1-defect Separation of isoforms Bio-informatics coupling with 4 public glyco-databases
23 WES + Glycomics profiling: MAN1B1 (Golgi mannosidase) 12 patients with unique profile: Known intellectual disability gene, +/- truncal obesity Van Scherpenzeel et al. Brain 2014
24 WES in 1 patient gives 8 candidate genes None of the 8 candidates in relevant homozygous interval Two affected adults with moderate intellectual disability, hypotonia, speech problems WES result: Homozygous: HRNR, C4ORF37, WDR41, TMCC3 Compound heterozygous: PLXNA4, PKHD1L1, DPAGT1, CKAP2 CONCLUSION: DPAGT1 Iqbal et al Eur J Hum Genet. 2013
25 3-MGA-uria type IV.unsolved: MEGDEL A Dystonia Deafness syndrome 3-MEthylGlutaconic acid 3y Sensorineural Deafness Encephalopathy Leigh-like features Neonatal hypoglycaemia Liver dysfunction Psychomotor retardation Muscle hypotonia / dystonia / progressive spasticity 16y Wortmann S. et al. Mol Genet Metab
26 Sanger Sequencing SERAC1 unknown function 18 patients from 16 families (2014: 38 patients) 16 different mutations 4 nonsense, 4 canonical splice site, 4 frameshift, 3 missense,1 in frame deletion Wortmann et al, Nature Genetics,2012
27 Barth Syndrome 3-MGA-uria OXPHOS dysfunction Low plasma cholesterol TAZ Cardiolipin remodeling MEGDEL Syndrome 3-MGA-uria OXPHOS dysfunction Low plasma cholesterol SERAC1 lipase domain positive filipin stainintracellular cholesterol accumulation??? Let s do phospholipid analysis
28 Phospholipid analysis of fibroblasts phosphatidylglycerol SERAC1 BMP PG 16:0/18:1 PG 18:0/18:1
29 Phospholipid metabolism in Barth and MEGDEL syndrome DAG Phosphatidic acid LPA Phosphatidyl glycerol unknown PG BMP 16:0 / 18:1 SERAC 1 / MEGDEL 18:0 / 18:1 syndrome TAZ Cardiolipin Remodeled cardiolipin Barth syndrome? (role in cholesterol trafficking) Wortmann S. et al. Nat Genet 2012
30 The functional genomics laboratory Early 20 th century set of case notes for Sir Archibald Garrod (Museum & Archive, Great Ormond Street Hospital for Children) The book of life: hoe lees je het weet wat je leest wat betekent het eigenlijk?
31
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