Reverse phenotyping: MCD Detection without clinical diagnosis. Diagnostic: NGS panels versus WES
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1 Clinical Genetics Leading the way in genetic issues Reverse phenotyping: MCD Detection without clinical diagnosis Diagnostic: NGS panels versus WES Martina Wilke Laboratory Specialist Clinical Genetics Dept. of Clinical Genetics Erasmus MC Rotterdam The Netherlands Milan, 19 June 2018
2 Declaration of Conflict of Interest I have no commercial disclosure
3 Malformations of Cortical Development (MCD) Week Central Nervous System Processes Abnormalities Time 1.Dorsal Induction Neural Tube Defects 3-7 w. 2.Ventral Induction Holoprosencefalie 5-6 w. 3.Neuronal Glial Proliferation Micro/Megalencefalie 8-16 w. 4.Migration Lissencefalie en heterotopia w. 5.Organization Polymicrogyrie, dysplasie >24 w. 6.Myelinatie Hypo/dysmyelinatie >24w.-2 yr.
4 The past: Sanger-sequencing (1) Abnormal proliferation of the cortex (micro- en macrocephaly) ERCC2, ERCC5, ERCC6, CEP152, EIF2AK3, WDR62, TSC1/ TSC2, AKT3 (2) Abnormal neuronal migration (lissencefalie/heterotopie) PAFAH1B1/LIS1 (+ MLPA), TUBA1A, DCX, RELN, ARX, WDR62, FLNA, ARFGEF2 (3) Abnormal organisation of the cortex and cerebrovascular abnormalities KIAA1279 / KBP, RTTN, GPR56, COL4A1, COL4A2 Disadvantage: (1) Time consuming; (2) Expensive Still important: clear defined phenotype
5 Single gene approach: 1227 patients Gene Nr of patients DCX 14/ 84 ARX 3/ 177 ARFGEF2 5/ PAFAH1B1 24 TUBA1A 6 FLNA 33 COL4A1 27/ 422 COL4A2 1 ADGRG1 3 KIF1BP 3 ERCC2 2 ERCC5 2 EIF2AK3 1 Total of 124 mutations in 13 different genes > 200 VUS
6 Diagnostic yield: Single gene approach 1227 individuals with cortical brain malformations Direct diagnosis: 89 (7,2%) After evaluation: 35 (2,8%) Total diagnostic yield: 10 %
7 Next Generation sequencing From genes (1) Abnormal proliferation of the cortex (micro- en macrocephaly) ASPM, MCPH1, STIL, CDK5RAP2, CENPJ, ATR, CEP152, PCNT, ERCC1, ERCC2, ERCC5, ERCC6, SLC25A19, CASK, TSEN54, EMG1, RNU4ATAC / U4actc snrna, NBS1, MYCN, JAM3, PNKP, MED17, VPS13B/COH1, DKC1, EIF2AK3, IER3IP1, ASXL1, LYK5/STRADA, TSC1/ TSC2, PTEN, AKT1, AKT3, PIK3R2, PIK3CA,TBC1D7, TUBB5, KIF5C, STAMBP, TBC1D20 (2) Abnormal neuronal migration (lissencefalie/heterotopia) PAFAH1B1/LIS1, TUBA1A, DCX, RELN, ARX, NDE1, WDR62, ACTB, ACTG1, LAMC3, FLNA, ARFGEF2, INTS8, YWHAE, ERMARD, DCHS1, FAT4, KIF2A,TUBG1 (3) Abnormal organisation of the cortex and cerebrovascular abnormalities TUBB2B, TUBB3, TUBA8, EOMES/TBR2, TBC1D24, OCLN, RAB3GAP1, RAB3GAP2, RAB18, CNTNAP2, SNAP29, VLDLR, SRPX2, COL18A1, PAX6, KIAA1279/KBP, ATP6V0A2, RTTN, GPR56, FKRP, LARGE, POMGnT1, POMT1, POMT2, FKTN, ISPD, COL4A1, COL4A2, AP4M1, AP4S1, AP4E1, L1CAM, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, RNASET2, SAMHD1, B3GALNT2, DYNC1H1, NSDHL, TMEM5, AP1S2, EML1 Sanger sequencing: ARX!Extra MLPA analyse (SALSA P061 Lissencephaly probemix; MRC Holland)!
8 NGS-targeted: Targeted gene panel: Enrichement for a group of genes Beter coverage, cheaper, simple analysis (relative) No unsolicited findings Turn around time Disadvantage: self design, less flexibel than WES
9 Targeted capture/enrichment Bait design: 103 genes>1600 fragments (Agilent Sure Select Quality check (3 parameters) Sample prep/ Run Miseq; 12 patients/ run Mapping of data to the whole genome, average coverage ca. 300x Variant calling: SeqNext (JSI) Classification: Alamut!Extra: MLPA (SALSA P061 Lissencephaly; MRC Holland)
10 Variant classification: Rest-Variants after filtering Classification sequence variants - Class 1; benign (frequent in control populations) Not reported - Class 2; silent variants and intronic variants, without effect on Not reported - Class 3; Rest group (VUS) Further investigation possible - Class 4; Probably pathogenic, HGMD link; earlier seen in patients Prenatal diagnosis and family testing (in aggreement only) Class 5; pathogenic (frameshift, nonsense, splicesite (+/- 1 and 2)) Prenatal diagnosis/ presymptomatic testing Make a choice for which variant will be reported and/or confirmed by Sanger sequencing Discusison MEG: Do genotype/ fenotype match (GENEMATCHER) further investigation(s). Wallis et al (ACGS & VKGL; 2013) Practice guidelines for the evaluation of pathogenicity and the reporting of sequence variants in Clinical Molecular Genetics
11 NGS-targeted: Pathogenic mutations (August Spring 2016) Gene Mutation Inheritance ACTB c.625g>a, p.val209met AD ASPM c.3202g>t, p.glu1068* AR CENPJ c.289dupa, p.thr97fs AR CENPJ c.1805_1808del, p.glu602fs AR CEP152 c.4000_4001delaa, p.lys1334fs AR CEP152 c.467dupg, p.gln157fs AR COL18A1 c.3512_3515delct, p.leu1172valfs AR COL18A1 c.2368c>t, p.arg780* AR COL4A1 c.324+1g>a, p.? AD DCX c.587g>a, p.arg196his X-Linked DCX c.907c>t, p.arg303* X-Linked DYNC1H1 c.3359a>g, p.tyr1120cys AD DYNC1H1 c.3185a>c, p.asp1062ala AD ERCC2 c.1381c>g, p.leu461val AR FLNA c.5160c>a, p.tyr1720* X-Linked FLNA c.4310_4314del, p.pro1437fs X-Linked INTS8 c.1665_1699del5inst, p.leu565phefs NN/AR KIF2A c.962a>c, p.his321pro AD PAFAH1B1 c.1111c>t, p.arg371* AD PAFAH1B1 c.337c>t, p.arg113* AD PIK3CA c.241g>a, p.glu81lys AD PIK3R2 c.1117g>a, p.gly373arg AD PNKP c.1253_1269dup17, p.thr424fs AR PNKP c g>t, p.? AR PNKP c.793a>g, p.met265val AR PTEN c.45a>c, p.arg15ser AD RAB3GAP1 c.748+1g>a, p.? AR RAB3GAP2 c.1361_1370del10, p.asn454fs AR RAB3GAP2 c.265dupa, p.met89fs AR RELN c.4228g>a, p.glu1410lys AR RELN c.6866c>t, p.thr2289ile AR RNASE2B c.529g>a, p.ala177thr AR RNU4ATAC g c>t, p.? AR RNU4ATAC g c>t, p.? AR RNU4ATAC g c>t, p.? AR RTTN c.31+1g>t, p.? AR SLC25A9 c.720delc, p.phe240fs AR TBC1D24 c.1008delt, p.his336fs AR TREX1 c.490dupa, p.cys154fs AD/AR TSC2 c.4604a>c, p.asp1535ala AD TSEN54 c.3_8dup, p.glu6_pro7dup AR TSEN54 c.919g>t, p.ala307ser AR TUBA1A c.791g>a, p.arg264his AD TUBB2B c.292g>a, p.gly98arg AD TUBB3 c.211g>a, p.gly71arg AD VPS13B c.626-1g>c, p.? AR Total 46 pathogenic mutations; 22 likely pathogenic mutations in 32 different genes > 600 VUS
12 Diagnostic yield: Targeted NGS 251 individuals with cortical brain malformations Direct diagnosis: 18 (7,2%) After evaluation: 12 (4,8%) Total diagnostic yield: 12 %
13 Diagnostic Yield depends on phenotyping
14 WES in DNA diagnostic Why? Patients genetically very heterogenous Same method for all panels: less money; less time Clinical Research Exome (CRE) (beter coverage disease genes) Diagnostic yield will increase Flexibel; genepanels can be expanded regularly (2x/ year) Open exome after (trio- analysis) is possible Whole Genome Sequencing Too expensive (at the moment) From 103 genes 172 genes WES-CRE-NEUMIG
15 Technical Information: WES-CRE NEUMIG Quality check 96 patients/1 run Agilent SureSelect Clinical Research Exome V2 capture (paired end sequenced /Illumina platform (outsourced). Average coverage of the exome is ~50x. Duplicate reads are excluded. Mapping to the genome: BWA MEM algorithm (reference: bwa.sourceforge.net/) Variant detection: Genome Analysis Toolkit HaplotypeCaller (reference: Filtering and annotation: Cartagenia software Classification with Alamut Visual!Extra: MLPA (SALSA P061 Lissencephaly; MRC Holland)
16 WES-CRE: Pathogenic Mutations (Spring 2016) Gene Mutation Inheritanc e ANKLE2 c g>c, p.? AR AP4M1 c.1317g>a, p.trp439* AR AP4M1 c.1012c>t, p.arg338* AR ASNS c.1002t>g, p.tyr334* AR ASPM c.2495dupa, p.tyr832* AR ASPM c.8563a>t, p.arg2855* AR CENPJ c.3595c>t, p.gln1199* AR CRB2 c.2887_2905del19, p.met963fs AR ERCC2 c.1816g>t, p.glu606* AR ERCC2 c.1381c>g, p.(leu461val) AR ERCC2 c.2150c>g, p.(ala717gly) AR ERMARD c.1369_1373dup5, p.leu459fs AD FLNA c.6052g>t, p.glu2018* X-linked ISPD c.679c>t, p.gln227* AR KIF11 c.1078_1085del, p.leu360alafs*2 AD KIF5C c.2708g>a, p.(arg903his) AD LAMA1 c.2755g>a, p.(gly919arg) AR LAMA1 c.2657c>t, p.(ala886val) AR LAMC c.976+1g>a, p.? AR PAFAH1B1 c.430c>t, p.arg144* AD PLK4 c.1299_1300ins20, p.lys434* AR PLK4 c.1199_1200insgaa, p.his400delinsglnasp AR POMGNT1 c.880-1g>c, p.? AR POMGNT1 c.187c>t, p.arg63* AR PTEN c.355g>t, p.(val119phe) AD PTEN c.518g>a, p.(arg173his) AD PTEN c.511c>t, p.gln171* AD PTEN c.959t>a, p.leu320* AD RNASEH2B c.529g>a, p.(ala177thr) AR RNASEH2B c.136+1delg, p.? AR TREX1 c.309dupc, p.thr104fs AD TSC2 c.1864c>t, p.(arg622trp) AD TUBA1A c.641g>a, p.(arg214his) AD TUBA1A c.788c>t, p.(pro263leu) AD VLDLR c t>a, p.? AR VPS13B c.8978a>g, p.(asn2993ser) AR WDR81 c.4668_4669delag, p.gly1557fs AR 37 pathogenic / 8 likely pathogenic mutations in 25 different genes. > 232 Variants of unknown significants
17 Diagnostic yield: WES-CRE 108 individuals with cortical brain malformations Direct diagnosis: 8 (7,4%) After evaluation: 12(11,1%) Total diagnostic yield: 18,5 %
18 Conclusions: Both approaches are suited (Advantages/ disadvantages) Feedback required for interpretation of VUS: genotype/ phenotype correlation Diagnostic yield improves after evaluation of results Close collaboration of a Multidisciplinary Expert Group is mandatory for the diagnosis of complex MCD patients
19 Acknowledgements: Diagnostic Laboratory Marjon van Slegtenhorst Marianne van Tienhoven Galhana Bolman Joan Kromosoeto Rick van Minkelen Walter de Valk Department Clinical Genetics Dicky Halley Counseling: Grazia Mancini Alice Brooks (Maartje Berghuis) (Renske Oegema) Rachel Schot Functional unit: Frans Verheijen Medical expertise team: MEG-NEUMIG Sequencing: Dept. of Biomics, Erasmusmus MC, The Netherlands GenomeScan B.V., Leiden, The Netherlands
20 Q&A
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chr6: _ del HFE NM_ ,744 bp deletion Deletion of entire HFE gene 2
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b 0.50 Synonymous Subtype
omatic mutation count Mutations per Mb a 80 * b 0.50 ynonymous 60 0.40 Non-synonymous 40 0.30 0.20 20 0.10 c 0 Fibroadenoma Phyllodes 0.00 ubtype Benign Borderline MAL upplementary Figure 1 Landscape of
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p.arg119gly p.arg119his p.ala179thr c.540+1g>a c.617_633+6del Prediction basis structure
a Missense ATG p.arg119gly p.arg119his p.ala179thr p.ala189val p.gly206trp p.gly206arg p.arg251his p.ala257thr TGA 5 UTR 1 2 3 4 5 6 7 3 UTR Splice Site, Frameshift b Mutation p.gly206trp p.gly4fsx50 c.138+1g>a
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