DIAGNOSTICS THROUGH MICROARRAY POSTNATAL DIAGNOSIS

Transcription

1 DIAGNOSTICS THROUGH MICROARRAY POSTNATAL DIAGNOSIS

2 COMPANY PROFILE Microgenomics S.r.l. is a spin-off company of the University of Pavia founded by the research team of Molecular Cytogenetics of the Department of Molecular Medicine. The Microgenomics laboratory is a highly specialized diagnostic center providing molecular investigation services based on the array-cgh technology. Specialists working in the Microgenomics laboratory are considered, in Italy and abroad, leading experts in the fields of molecular cytogenetics, genomics and microarray analysis, as shown by the numerous publications in major scientific journals and the lectures, on invitation, at the most prestigious international scientific conferences on genetics. R&D activity is an essential element of Microgenomics laboratory. The aims of which are qualitative excellence, implementation of new diagnostic technologies and optimization of those already used in the laboratory. ARRAY-CGH The array-based Comparative Genomic Hybridization (array-cgh or molecular karyotype) is a molecular cytogenetic technique developed to identify Copy Number Variants (CNVs), such as deletions (loss of genomic portions) and amplifications (presence of extra copies of DNA segments), which may be responsible for malformative syndromes, mental retardation, autism, epilepsy and cancer. Array-CGH can detect genomic deletions or amplifications with far greater sensitivity ( times) than can be achieved by conventional chromosome analysis. The Microgenomics laboratory uses high resolution, oligonucleotide-based array- CGH technique for genomic investigations aimed to identify possible disease causing genomic alterations.

3 SERVICES POSTNATAL DIAGNOSIS Nowadays molecular karyotyping is considered a first-tier diagnostic test for individuals with unexplained mental retardation, developmental delay, autism spectrum disorders, epilepsy or multiple congenital anomalies. It has been demonstrated that molecular karyotype guarantees a much higher diagnostic yield (15%-20%) than conventional karyotype (~3%). Microgenomics utilizes different types of array platforms including genomewide arrays, ISCA arrays, and the MicrogenChip arrays developed by this laboratory. Both ISCA and MicrogenChip arrays can detect pathogenic imbalances throughout the genome but can also investigate disease-genes with very high resolution, increasing the sensitivity of the test. The MicrogenChip 180K and MicrogenChip 180K CGH+SNP arrays have been specifically designed for the application of molecular karyotype in postnatal diagnosis. These platforms are continuously updated with new disease genes in order to improve the sensitivity of the array-cgh analysis. MicrogenChip 180K array allows investigation at high resolution of about 500 genomic regions, including telomeric and pericentromeric regions and more than 390 loci associated with congenital malformations and syndromic mental retardation. MicrogenChip 180K CGH+SNP array contains SNP probes that allow to identify uniparental disomies, LOH and low-grade mosaicisms.

4 MICROGENCHIP 180K LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM 1p36 GABRD Idiopathic generalized epilepsy q23 BMPR1A Cowden p36 SKI 1p36 Microdeletion q23 PTEN PTEN-related disorders p36 TP73 1p36 Microdeletion q23 SLC16A12 1p36 KCNAB2 Focal epilepsy q23 LGI1 Cataract, juvenile, with microcornea A and glucosuria Autosomal dominant lateral temporal lobe epilepsy (ADLTE) p34 SLC2A1 Glucose transport defect q24 Split hand and foot malformation p34 POMGNT1 MDDGA q24 FGF8 Hypogonadotropic hypogonadism p33 AGBL4 Autism q25 SMC3 Cornelia de Lange p31 NFIA NFIA haploinsufficiency q26 EMX2 Schizencephaly p21 COL11A1 Stickler p15 Beckwith-Wiedemann / Silver-Russell p12 NOTCH2 Alagille p15 SOX6 Craniosynostosis q21 Thrombocytopenia absent radius p15 ABCC8 Familial hyperinsulinemic hypoglycemia q21 1q21.1 recurrent microdeletion/ microduplication / p15 USH1C Ushers 1C q21 CHRNB2 Nocturnal frontal lobe epilepsy type p13 WAGR q22 1q25 LMNA LHX4 Emery-Dreifuss muscular dystrophy / Werner /Hutchinson-Gilford Progeria Pituitary hormone deficiency, combined, p13- p14 PAX6 Aniridia p13 WT1 Wilms tumor q32 IRF6 Van der Woude p11 Potocki-Shaffer q41 DISP1 Fryns q13 NRXN2 Autism 1q42 TBCE Hypoparathyroidism retardation dysmorphism q13 NDUFV1 Mitochondrial complex I deficiency p14 GATA3 Hypoparathyroidism, sensorineural deafness, and renal disease q13 SHANK2 Autism q11 RET Hirschsprung disease plus q13 DHCR7 Smith-lemli-opitz q11 10q11.2 deletion 11q14 FZD4 Exudative vitreoretinopathy q21 EGR2 Autism q24 CDON Holoprosencephaly q22 KCNMA1 Generalized epilepsy and paroxysmal dyskinesia q24 KIRREL

5 LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM 11q24 KCNJ1 Bartter q22 SIX1 Branchiootorenal p13 CACNA1C Timothy q32 14q32.2 imprinted region paternal and maternal upd(14)- like phenotypes p13 GRIN2B Mental retardation, epilepsy q32 DYNC1H1 Charcot-Marie-Tooth disease type q13 COL2A1 Stickler q11- q13 15q11.2 deletion syndrome 12q13 TUBA1A/ TUBA1B Lissencephaly q11- q13 Angelman / Prader Willi / q13 MLL2 Kabuki q13 15q13.3 Microdeletion q14 LEMD3 Osteopoikilosis q21 SLC12A1 Bartter q24 PTPN11 Noonan q21 FBN1 Marfan q14 TBX5 Holt-Oram q24 15q24 Microdeletion q24 TBX3 Ulnar-mammary q26 CHD2 Scoliosis + CHARGE-like q12 GJB2 Deafness q26 NR2F2 Congenital diaphragmatic hernia q12 B3GALTL Peters-plus q25 IGF1R IGF-1 resistance q13 RXFP2 Cryptorchidism, unilateral or bilateral p13 HBA1& HBA2 Alpha thalassemia mental retardation q14 RB1 Retinoblastoma p13 CACNA1H Idiopathic generalized epilepsy q14 ATP7B Wilson disease p13 TSC2 Tuberous sclerosis q22 EDNRB Hirschsprung disease plus p13 PKD1 Polycystic kidney disease q32 ZIC2 Holoprosencephaly p13 CREBBP Rubinstein-Taybi q11 CHD8 Autism p13 A2BP1 Epilepsy, mental retardation q12 FOXG1 Rett, congenital variant p13 GRIN2A Mental retardation, epilepsy q13 PAX9 Selective tooth agenesis p13 16p13.1 Microdeletion predisposition to autism 14q22 BMP4 Microphthalmia with brain and digital anomalies p11- p12 16p11.2-p12.2 Microdeletion/ microducplication q22 OTX2 Microphthalmia syndromic p11 16p11.2 Microdeletion/microducplication q22 SIX6 Microphthalmia q12 SALL1 Townes brocks

6 LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM 16q13 GPR56 Bilateral frontoparietal polymicrogyria p13 STK11 Peutz-Jeghers q21 CDH8 Autism p13 NOTCH3 CADASIL q22 CBFB Delayed cranial ossification q13 SCN1B Generalized epilepsy with febrile seizures plus q24 CDH q13 RPS19 Diamond blackfan anemia q24 ANKRD11 KBG syndrome p24 MYCN Feingold p13 ASPA Canavan p22 SOS1 Noonan p13 Miller-Dieker p21 Cystinuria with mitochondrial disease p13 TP53 Li-Fraumeni p21 SIX3 Holoprosencephaly p12 PMP22 Charcot marie tooth disease 1A p16 NRXN1 Autism p11 RAI1 Smith-magenis p15 2p15-p16.1 Microdeletion q11 NF1 Neurofibromatosis Type q14 GLI2 Holoprosencephaly q12 HNF1B Reanal cysts and diabetes q22 ZEB2 Mowat-Wilson q21 SOST Sclerosteosis q23 MBD5 Mental retardation q21 17q21.31Microdeletion q23 CACNB4 Idiopathic generalized epilepsy type q21 COL1A1 Osteogenesis imperfecta q24 SLC4A10 Autism, epilepsy, mental retardation q24 Pierre Robin/sex reversal/cooks/ campomelic dysplasia / / q24 SCN3A Infantile epilepsy q24 SOX9 Campomelic dysplasia q24 SCN2A Early infantile epileptic encephalopathy type q25 CSNK1D/ SLC16A3 Autism q24 SCN1A SCN1A related seizures p31 TGIF1 Holoprosencephaly q24 SCN9A Generalized epilepsy with febrile seizures plus q12 SETBP1 Schinzel-Giedion q31 SLC25A12 Hypomyelination, global, cerebral q21 DYM Dyggve-Melchior-Clausen disease q31 EVX2 Synpolydactyly q21 SMAD4 Hereditary hemorrhagic telangiectasia q31 HOXD gene cluster q21 TCF4 Pitt-Hopkins q32 SATB2 Cleft palate

7 LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM 2q33 BMPR2 Primary pulmonary hypertension p25 VHL Von hippel lindau q36 PAX3 Waardenburg p25 RAF1 Noonan q37 HDAC4 Brachydactyly-mental retardation p24 TGFBR2 Marfan q37 KIF1A p21 TDGF1 Mental retardation and holoprosencephaly p12 JAG1 Alagille p14 MITF Waardenburg IIA q11 ASXL1 Bohring-Opitz syndrome p13 FOXP1 20q11 GDF5 Brachydactyly type C q21 CASR 20q11 EPB41L1 11 Intellectual disability, autism, and language impairment Autosomal dominant hypocalciuric hypocalcemia q22 FOXL2 BPES q13 SALL4 Okihiro q24 SLC9A9 Autism q13 GNAS Albright hereditary osteodystrophy q24 c3orf58 Autism q13 CHRNA4 Nocturnal frontal lobe epilepsy type q24 ZIC4/ZIC1 Dandy-Walker q13 KCNQ2 Familial neonatal seizures type q26 PDCD10 Cerebral cavernous malformations type 3 (CCM3) q21 GRIK1 Juvenile absence epilepsy type q26 SOX2 Microphthalmia q21 22q11 DYRK1A 7 DGVCF/Microduplication q27 CLCN / q28 TP63 ADULT/EEC3 Idiopathic generalized epilepsy type / q11 TBX1 digeorge q29 3q29 Microdeletion/microduplication q12 NF2 Meningioma/NF / p16 FGFR3 Muenke/achondroplasia/thanatophoric dysplasia type I (TD1) / / MICROGENCHIP 180K 22q12 CACNG p16 WHSC1 Wolf-hirschhorn q13 SOX10 Waardenburg 4C p16 WHSC2 Wolf-hirschhorn q13 EP300 Rubinstein-Taybi p16 PPP2R2C Mental retardation, epilepsy q13 22q13 Microdeletion (Phelan McDermid) q22 PKD2 Polycystic kidney disease q13 SHANK3 Autism, mental retardation q25 PITX2 Rieger

8 MICROGENCHIP 180K LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM 5p13 NIPBL Cornelia de Lange p14 GLI3 Greig cephaloplysindactyly q14 MEF2C Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations p13 CCM2 Cerebral cavernous malformations type 2 (CCM2) q14 GPR98 Familial febrile seizures type p12 GRB10 Silver-Russell q22 APC Gardner q11 5q23 LMNB1 Adult-onset autosomal dominant leukodystrophy Williams-Beuren microdeletion/ microduplication q11 7q11.23 Distal Deletion q32 SPINK1 Chronic pancreatitis q21 MAGI2 Infantile spasms q33 TCOF1 Treacher Collins q21 KRIT1 Cerebral cavernous malformations type 1 (CCM1) q34 GABRA1 Juvenile myoclonic epilepsy type q21 COL1A2 Ehlers-danlos q34 5q35 GABRG2 FBXW11 Familial febrile seizures type 8/ childhood absence epilepsy type 2 Holoprosencephaly and preaxial polydactly / q35 MSX2 Craniosynostosis q22 RELN 7q21 SGCE Myoclonic dystonia q21 Split hand and foot malformation Lissencephaly with cerebellar hypoplasia q35 NSD1 Sotos q31 FOXP2 Verbal dyspraxia p25 TUBB2B Asymmetric polymicrogyria q31 KCND2 Temporal lobe epilepsy p24 FOXC1 6p24 Deletion q31 CADPS2 Autism p21 6p21 SYNGAP1 VEGFA 5 Vascular endothelial growth factor disorders q35-36 CNTNAP2 Autism q36 EN2 Autism p21 RUNX2 Cleidocranial dysplasia q36 SHH Holoprosencephaly p12 6q16 EFHC1 GRIK2 Juvenile absence epilepsy type 1/ juvenile myoclonic epilepsy type 1 Mental retardation, autosomal recessive / q36 LMBR1 Polydactyl preaxial q36 MNX1 Currarino q24 PLAGL1 Diabetes mellitus, transient neonatal, p23 DLGAP2 Autism p21 TWIST1 Saethre-Chotzen p23 GATA4 Congenital heart defects

9 LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM 8p21 CHRNA2 Nocturnal frontal lobe epilepsy type Xp22 PAR1 8p12 FGFR1 Kallmann Xp22 SHOX Leri-Weill dyschondrostosis (LWD) - SHOX deletion q12 CHD7 CHARGE Xp22 ARSE Chondrodysplasia punctata X-linked q13 EYA1 Branchio-oto-renal Xp22 NLGN4 Autism, mental retardation q21 8q21.11 Microdeletion Syndrome Xp22 STS Steroid sulfatase q23 ZFPM2 Diaphragmatic hernia Xp22 KAL1 Kallmann q23 TRPS1 Trichorhinophalangeal Xp22 HCCS Microphthalmia with linear skin defects q24 EXT1 Trichorhinophalangeal 2 (Langer- Giedion) Xq22 MID1 Opitz q24 KCNQ3 Familial neonatal seizures type Xp22 OFD1 Orofaciodigital q24 KCNK9 Birk-barel mental retardation dysmorphism Xp22 AP1S2 X-linked mental retardation p24 DMRT1 9p24 Microdeletion Xp22 NHS Nance-horan p24 DMRT2 9p24 Microdeletion Xp22 CDKL5 early infantile epileptic encephalopathy q22 PTCH1 Holoprosencephaly Xp22 PDHA1 Pyruvate decarboxylase deficiency q22 TGFBR1 Loeys-Dietz Xp22 RPS6KA3 Coffin-lowry q33 NR5A1 XY Sex Reversal Xp22 SMS Snyder-Robinson q33 LMX1B Nail-patella Xp22 PHEX Hypophosphatemic rickets q34 STXBP1 Early infantile epileptic encephalopathy Xp22 DDX53/ PTCHD1 Autism q34 ENG Hereditary hemorrhagic telangiectasia Xp21 ARX Early infantile epileptic encephalopathy q34 SPTAN1 Early infantile epileptic encephalopathy type Xp21 IL1RAPL1 X-linked mental retardation q34 TSC1 Tuberous sclerosis Xp21 NR0B1 Adrenal hypoplasia congenita q34 POMT1 MDDGA Xp21 GK Glycerol kinase deficiency q34 GRIN Xp21 DMD Duchenne muscular dystrophy q34 EHMT1 9q34.3 Microdeletion CYBB Chronic granulomatous disease

10 LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM OTC Ornithine transcarbamylase deficiency PHF8 Syndromic X-linked mental retardation, Siderius type TSPAN7 X-linked mental retardation FGD1 Aarskog-Scott BCOR Syndromic microphthalmia Xq11 ARHGEF9 Hyperekplexia and epilepsy ATP6AP2 X-linked mental retardation with epilepsy Xq12 AR Androgen insensitivity CASK MICPCH Xq12 OPHN1 X-linked mental retardation, with cerebellar hypoplasia and distinctive facial appearance MAOA Brunner Xq13 EFNB1 Craniofrontonasal NDP Norrie Xq13 EDA Ectodermal dysplasia ZNF674.3 deletion Xq13 DLG3 X-linked mental retardation RP2.3 deletion Xq13 MED12 Opitz-Kaveggia ZNF41 X-linked mental retardation Xq13 ZMYM3 X-linked mental retardation SYN1 Epilepsy, X-linked, with variable learning disabilities and behavior disorders Xq13 NLGN3 Autism ZNF81 X-linked mental retardation Xq13 SLC16A2 Allan-Herndon-Dudley FTSJ1 X-linked mental retardation Xq13 KIAA2022 X-linked mental retardation p11.22 duplication Xq13 ZDHHC15 X-linked mental retardation PORCN Focal dermal hypoplasia Xq21 ATRX Alpha thalassemia mental retardation PQBP1 Renpenning Xq21 ATP7A Menkes SYP X-linked mental retardation SYP-related Xp21 PGK1 Phosphoglycerate kinase-1 deficiency CLCN5 Nephrolithiasis 2, X-linked/dent disease / Xp21 BRWD3 X-linked mental retardation SHROOM4 Stocco dos Santos X-linked mental retardation Xq21 ZNF711 X-linked mental retardation KDM5C Syndromic X-linked mental retardation JARID1C-related Xp21 CHM Choroideremia SMC1A Cornelia de Lange X-linked Xq22 TIMM8A Deafness-dystonis-optic neuronopathy HSD17B10 HSD10 deficiency/syndromic X- linked mental retardation / Xq22 SRPX2 Rolandic epilepsy, X-linked mental retardation, and speech dyspraxia HUWE1 Syndromic X-linked mental retardation, Turner type Xq22 PCDH19 Early infantile epileptic encephalopathy type

11 LOCUS GENE SYNDROME/DISEASE OMIM LOCUS GENE SYNDROME/DISEASE OMIM Xq22 BTK Agammaglobulinemia, X-linked Xq26 ARHGEF6 X-linked mental retardation Xq22 GLA Fabry disease Xq26 ZIC3 X-linked heterotaxy Xq22 PLP1 Pelizaeus-merzbacher disease Xq27 SOX3 Xq22 PRPS1 Charcot marie tooth disease X-linked Xq22 COL4A5 Alport, X-linked Xq28 EMD Xp22 ACSL4 X-linked mental retardation Xq28 AFF2 X-linked mental retardation with panhypopituitarism Xq27 FMR1 Fragile X Emery-dreifuss muscular dystrophy X-linked mental retardation associated with fragile site FRAXE Xp22 PAK3 X-linked mental retardation Xq28 IDS Hunter, Mucopolysaccharidosis type Xq22- q23 DCX X-linked lissencephaly/subcortical band heterotopia Xq23 AGTR2 X-linked mental retardation Xq28 SLC6A8 Xq23 Xq24 Xq24 UBE2A UPF3B NDUFA1 Syndromic X-linked mental retardation, UBE2A-related Syndromic X-linked mental retardation 14 X-linked mitochondrial complex I deficiency Xq28 MTM1 Myotubular myopathy Creatine deficiency / X-linked mental retardation Xq28 ABCD1 Adrenoleukodystrophy Xq28 L1CAM HSAS, MASA, CRASH Xq28 AVPR2 Diabetes insipidus, nephrogenic, X-linked / Xq24 LAMP2 Danon disease Xq28 MECP2 Rett Xq24 CUL4B X-linked mental retardation with short stature, hypogonadism, and abnormal gait Xq28 FLNA Heterotopia, periventricular, X- linked dominant Xq24 GRIA3 X-linked mental retardation Xq28 RPL10 Autism Xq25 OCRL Lowe Xq28 GDI1 X-linked mental retardation Xq25 ZDHHC9 Syndromic X-linked mental retardation ZDHHC9-related Xq28 IKBKG Incontinentia pigmenti Xq26 GPC3 Simpson, golabi, behmel, type Xq28 DKC1 X-linked dyskeratosis congenita Xq26 PHF6 Borjeson-forssman-lehmann Xq28 RAB39B X-linked mental retardation Xq26 HPRT1 Lesch-Nyhan Xq28 PAR2 Xq26 SLC9A6 X-linked mental retardation, christianson type Yp11 SRY Gonadal dysgenesis SRY-related v. 2.0 (last update: 03/2012) MICROGENCHIP 180K

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