Preconceptional Test For Monogenic Diseases

Transcription

1 Preconceptional Test For Monogenic Diseases Dr. José A. Horcajadas Associate Professor, U. Pablo de Olavide, Seville, Spain Research Associate Professor, EVMS, Norfolk, Virginia, US CSO, Recombine Europe, Barcelona, Spain 1

2 The Human Genome Project started in 1990 ² The Mission of the HGP: The quest to understand the human genome and the role it plays in both health and disease. The true payoff from the HGP will be the ability to better diagnose, treat, and prevent disease. --- Francis Collins, Director of the HGP and the National Human Genome Research Institute (NHGRI)

3 1985-Human Genome Project Lord, They discover the complete Human Genome code! FINISHED!!! Heavens! Those hackers! I have to change the password!

4 HUMAN GENOME PROJECT + NEW TECHNOLOGIES = THE OMICS REVOLUTION

5 Quackenbush 2006 N Engl J Med 354:

6 TRADITIONAL VERSUS OMICS APPROACHES

7 The Basic Paradigm of the Biology

8 PGD/PGS PRENATAL PRECONCEPTIONAL

9

10 GENETIC BASIS OF DISEASE Complexity of the Human Genome million pairs of bases Around genes 3% are genes, 97% is junk DNA with some regulatory acevity over those genes (not anymore junk!) We all share >99% of geneec informaeon, with >20 million pairs of bases (SNPs) being different.

11 SNPs SNPs (single nucleoede polymorphisms) are one base change (A,T,C,G) in the DNA sequence. SNPs explain many geneec diseases and differences between humans. Close to 20M SNPs idenefied

12 THE BURDEN OF GENETIC DISEASE Autosomal Recessive Inheritance single gene disorders Combined incidence: 1/300 births (U.S.) 20% infant deaths Everyone carries severe recessive mutajons that can cause geneec condieons Recessive mutaeons can pass down quietly through many generaeons Carriers may not have a family history or symptoms of a geneec disease Hence, carrier tesjng is the only way to determine carrier status 1. Bell, C.J., Dinwiddie, D.L., Miller, N.A., Hateley, S.L., Ganusova, E.E., Mudge, J., Langley, R.J., Zhang, L., Lee, C.C., Schilkey, F.D., Sheth, V., Woodward, J.E., Peckham, H.E., Schroth, G.P., Kim, R.W., Kingsmore, S.F., Carrier teseng for severe childhood recessive diseases by next- generaeon sequencing. Sci Transl Med. Jan 12;3(65):65ra4 2. Berry, R.J., Buehler, J.W., Strauss, L.T., Hogue, C.J., Smith, J.C., Birth weight- specific infant mortality due to congenital anomalies, 1960 and Public Health Rep. 102, Costa, T., Scriver, C.R., Childs, B., The effect of Mendelian disease on human health: a measurement. Am. J. Med. Genet. 21, Gukmacher, A.E., Collins, F.S., Genomic medicine: a primer. N. Engl. J. Med. 347, Kingsmore, S., Comprehensive carrier screening and molecular diagnosec teseng for recessive childhood diseases. PLoS Curr. May 2:e4f9877ab8ffa9. 6. Kumar, P., Radhakrishnan, J., Chowdhary, M.A., Giampietro, P.F., Prevalence and pakerns of presentaeon of geneec disorders in a pediatric emergency department. Mayo Clin. Proc. 76, Scriver, C.R., Neal, J.L., Saginur, R., Clow, A., The frequency of geneec disease and congenital malformaeon among paeents in a pediatric hospital. Can. Med. Assoc. J. 108, Srinivasan, B.S., Evans, E.A., Flannick, J., Pakerson, A.S., Chang, C.C., Pham, T., Young, S., Kaushal, A., Lee, J., Jacobson, J.L., Patrizio P., A universal carrier test for the long tail of Mendelian disease. Reprod Biomed Online. Oct;21(4):

13 GENETIC DISORDERS AND SCREENING PaEents affected by rare disorders face muleple challenges (survey by Eurodis 2006): DiagnosEc delay (5-30 years for 25% of paeents) 40% inieally receive incorrect diagnosis 33% received inappropriate treatment: 16% unnecessary surgery 10% received Psychological care: Wrong assumpeon of psychosomaec basis

14 Great, great, great, great, great granduncle was the previous affected family member ~175 years earlier

15 Why should we recommend expanded carrier screening?

16 REASONS TO DO IT It has worked with other ethnic panels It is recommended for the specialists It is cheaper that the cost of maintaining the affected people Because populaeon is homogenizing and ethnicity panels are not valid

17 17 Genomic TesJng for Universal Carrier Status

18 NEW PARADIGM Test every couple planning to conceive for as many diseases as possible, affordably.

19 What diseases should be included in expanded screening?

20 CRITERIA FOR EXPANDED SCREENING: NIH In the NIH meeeng on PopulaEon- based Carrier Screening for Single Gene Disorders, the following criteria was recommended: Impaired health in homozygous affected offspring High frequency of carriers in screened populaeon Technically and clinically valid screening methods available Screening is cost- effeceve Consent is obtained IVF, prenatal diagnosis and terminaeon are reproduceve opeons PotenEal benefits and risks of carrier teseng are explained pre- and post- test Privacy is protected Experienced professionals are available SEgmaEzaEon of carrier status in the community is minimized The meeeng concluded that the top three consideraeons are: carrier frequency, disease burden and cost of screening. 1. hkp:// Last accessed: 9/20/2012

21 CURRENT GUIDELINES IN THE UNITED STATES ACMG & ACOG Cystic Fibrosis ACMG ACOG AJ Fragile X ACMG ACOG AJ Spinal Muscular Atrophy ACMG Hemoglobinopathies ACOG Bloom Syndrome ACMG AJ Canavan Disease ACMG ACOG AJ Familial Dysautonomia ACMG ACOG AJ Fanconi Anemia Type C ACMG AJ Gaucher Disease ACMG AJ Mucolipidosis Type IV ACMG AJ Niemann-Pick Type A ACMG AJ Tay-Sachs Disease ACMG ACOG AJ ACMG = American College of Medical Genetics & Genomics ACOG = American Congress of Obstetricians & Gynecologists AJ = Ashkenazi Jewish Screening Recommendations by ACOG/ACMG

22 Screening methods: SNP arrays

23 SINGLE NUCLEOTIDE POLYMORPHISM (SNP) MICROARRAYS Simultaneous analysis of 15,000 of SNPs and/or mutations Probes for each SNP allele are attached to a slide DNA sample

24 SNP MICROARRAYS T A T A A G G A T A A G A G C A A T T A G A G G A T T C T A T T C Heterozygous Homozygous C/T for C allele

25 Decrease HUMAN GENOME COST

26 The CarrierMap

27 THE RECOMBINE TEST We have created a chip to determine carrier status simultaneously for more than 300 geneec condieons by screening nearly 2,000 mutaeons. Our pan- ethnic screen includes diseases that are more common in specific ethnic groups as well as diseases that are less common or occur more broadly in the general populaeon. Recombine s test therefore provides the greatest reduceon to the overall risk of having a child with a geneec condieon.

28 CARRIERMAP TESTS FOR >300 GENETIC DISEASES CarrierMap is the most comprehensive genetic carrier screen available and follows all recommendations and guidelines from the leading organizations in reproduction and genetics. Useful for all patients, regardless of ethnicity. Common High Impact Conditions Cystic Fibrosis Fragile X Syndrome Spinal Muscular Atrophy Sickle-Cell Disease Alpha and Beta Thalassemia Tay-Sachs Disease Copyright Recombine

29 DISEASE LIST SELECTION CRITERIA INCLUSION: Autosomal recessive and/or X-linked recessive inheritance pattern Inclusion in ACOG/ACMG guidelines, and Jewish advocacy group recommendations Inclusion in state newborn screening guidelines Significant impact on life expectancy and/or quality of life, as defined by GC team High carrier rate in at least one population PGD previously performed for genetic disease Meets population-based screening criteria 1,2 Disease and/or mutation frequency studies published Inclusion in other carrier screening panels EXCLUSION: Autosomal dominant and/or multifactorial inheritance pattern Adult-onset disorder Limited or no impact on reproductive decisions (e.g. MTHFR deficiency) Low penetrance (e.g. HFE-related Hemochromatosis) 1. NIH meeting on Population-based Carrier Screening for Single Gene Disorders Last accessed: 9/ Watson, M.S., Lloyd-Puryear, M.A., Mann, M.Y., Rinaldo, P., Howell, R.R., Newborn Screening: Toward a Uniform Screening Panel and System. Genetics in Medicine. 8(5):12S-252S Copyright Recombine

30 DISEASE LIST EVOLUTION CRITERIA NEW DISEASES ADDED BASED ON: Emerging literature on natural history and frequency of diseases High carrier frequency in at least one population, particularly in in less well-represented populations (e.g. African, Latin American, Asian, Middle Eastern) Clinical impact affects areas that are less well-studied (e.g. ophthalmology) NEW MUTATIONS FOR EXISTING DISEASES ADDED BASED ON: Emerging literature on natural history and frequency of mutations Associated with diseases for which detection rate is relatively low (<40%) High frequency in at least one population Highly penetrant mutation DISEASES & MUTATIONS REMOVED BASED ON: Emerging literature on relatively low impact of disease and/or mutation Emerging literature on relatively low penetrance of disease and/or mutation Found to be unrelated to reproductive decision-making Copyright Recombine

31 RECOMBINE CARRIERMAP DISEASES HAVE SIGNIFICANT IMPACT 185+ Shortened Lifespan 145+ Cognitive Impairment 290+ Physical Impairment α-thalassemia Cystic Fibrosis ARPKD Fragile X Smith-Lemli-Opitz PKU SCID FMF β-thalassemia Copyright Recombine

32 Detection Rates Disease Gene (# Mutations) Ethnic Groups Detection Rate Carrier Rate Residual Risk Cystic Fibrosis CFTR (99) African American Ashkenazi Jewish Asian American European Hispanic ~81% ~97% ~55% ~93% ~77% 1/61 1/23 1/94 1/25 1/59 1/316 1/767 1/205 1/343 1/257 Spinal Muscular Atrophy SMN1 (Ex7 deletion) African American Ashkenazi Jewish Asian American European Hispanic ~71% ~90% ~93% ~95% ~91% 1/66 1/41 1/53 1/35 1/117 1/121 1/350 1/628 1/632 1/1,061 Bloom Syndrome BLM (2) Ashkenazi Jewish 97% 1/134 1/3,350 Canavan Disease ASPA (4) Ashkenazi Jewish European 99% 47% 1/55 Unknown 1/2,750 Unknown Familial Dysautonomia IKBKAP (3) Ashkenazi Jewish ~>99% 1/31 <1/3,000 Fanconi Anemia Type C FANCC (6) Ashkenazi Jewish ~99% 1/101 1/10,100 Gaucher Disease GBA (9) Ashkenazi Jewish ~96% 1/15 1/ Genetic Testing. Simplified. 32

33 Results: Carrier Rates Observed Copyright Recombine

34 SAMPLE SIZE & DEMOGRAPHICS v Sample size: 6,636 samples Analysis limited to samples tested on CarrierMap V3 Patient referrals from: endocrinologists, obstetricians, maternal-fetal medicine specialists, and genetic counselors 67% females, 33% males 33% 67% Females Males Copyright Recombine

35 DEMOGRAPHICS: ETHNICITY v Patient self-reported ethnicity 10 broadly defined ethnic groups, including Other 3% 11% 4% 1% 2% 5% 33% 13% 14% 6% 5% 67% 36% African East Asian European Jewish Latin American Mediterranean Middle Eastern Native American South Asian South East Asian Other Copyright Recombine

36 RESULTS: QUICK OVERVIEW 56% of patients identified as carriers for any disease 39% of patients identified as carriers for high impact disease 1.9% of couples identified as carriers for same disease 172 diseases, 534 mutations detected in total Copyright Recombine

37 RESULTS: HIGH IMPACT DISEASES Disease Counts Percentage Familial Mediterranean Fever 1/ % Spinal Muscular Atrophy 1/17 5.9% Cystic Fibrosis 1/19 5.2% Nonsyndromic Hearing Loss & Deafness: GJB2-Related 1/31 3.2% Alpha Thalassemia 1/51 2.0% Congenital Disorder of Glycosylation: Type 1A: PMM2 Related 1/51 2.0% Phenylalanine Hydroxylase Deficiency 1/77 1.3% Smith-Lemli-Opitz Syndrome 1/77 1.3% Autosomal Recessive Polycystic Kidney Disease 1/77 1.3% Beta Thalassemia 1/77 1.3% Copyright Recombine

38 OBSERVED > REPORTED FREQUENCIES Disease Carrier Rate in General Population Observed Reported Smith-Lemli-Opitz Syndrome 1/47 1/71 GSD Type II: Pompe Disease 1/72 1/97 Nonsyndromic Hearing Loss & Deafness: GJB2 Related 1/19 1/43 Gaucher Disease 1/75 1/112 Bardet-Biedl Syndrome: BBS1 Related 1/168 1/376 Walker-Warburg Syndrome 1/59 1/ Copyright Recombine

39 COUPLES CARRIER OF THE SAME DISEASE ~ 1,9% Couples are carriers of the same disease 29/1479 *Kumar, N., Bisignano, A., Asgari, S., Chu, B., Munne, S., Grifo, J., Berkeley, A., Licciardi, F., Chen, S., Hoffman, D., Barrionuevo, M., Prates, R. October From Carrier Screening to Single Gene PGD: An Analysis of 1/479 Couples Screened via an Expanded Carrier Screening Platform. ASRM 2014.

40 PGD for gene disorders We can do PGD for any of the 6000 diseases provided the mutajon is known Disease tested: Acetil Co Oxidase type I defficiency, Adrenoleucodistrophy, Alpha-thalassemia, Alport syndrome, Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recesive Polycystic Kidney Disease (ARPKD), Beta-thalassemia, Branchio-Oto-Renal syndrome (BOR), BRCA1 breast cancer predisposition, BRCA2 breast cancer predisposition, CanavanCharcot-Marie-Tooth type IA (CMT1a), Choroideremia, Congenital adrenal hyperplasia (CAH), Congenital neutropenia, Connexin 26 hearing loss, Cystic fibrosis, Duchenne/Becker Muscular Dystrophy (DMD), Ectrodactyly, Ectodermal dysplasia, and Cleft lip/palate syndrome (EEC1), Fabry Disease, Familial adenomatous poliposis coli (FAP), Familial dysautonomia, Familial intrahepatic cholestasis 2, Fanconi anemia, Fragile site mental retardation, Gangliosidosis type 1 (GM1), Gaucher disease, Glomuvenous malformations (GVM), Glycogen-storage disease type I (GSD1), Glycosylation type 1C, Hemoglobin SC disease, Hemophilia A, Hemophilia B, Hereditary nonpolyposis colon cancer (HNPCC), Hereditary pancreatitis, HLA matching Huntington disease, Hurler syndrome, Hypophosphatasia, Incontinential pigmenti, Krabbe disease (Globoid cell leukodystrophy), Long QT syndrome, Marfan syndrome, Meckle gruber, Metachromatic leukodystrophy (MLD), Methylmalonic aciduria cblc type (MMACHC), Myotonic Dystrophy 1, Myotubular myopathy, Neurofibromatosis 1, Neurofibromatosis 2, Niemann-Pick Disease, Noonan syndrome, Oculocutaneous albinism 1 (OCA1), Ornithine carbamoyltransferase deficiency (OTC), Osteogenesis Imperfecta 1, Rapp Hodgkin ectodermal dysplasia, Retinitis pigmentosa, Retinoblastoma, Sickle Cell Anemia, Smith- Lemli-Opitz syndrome (SLOS), Spinal bulbar muscular atrophy (SBMA), Spinal Muscular Atrophy Type 1 (SMA1), Tay Sachs, Tuberous sclerosis 1 (TSC1), Tuberous sclerosis 2 (TSC2), Von Hippel-Lindau Syndrome (vhl), X-linked dominant Charcot Marie Tooth (CMTX), etc (see review Gutierrez et al. (2008))

41 SUMMARY DISEASES FOUND IN COUPLES High impact disease Carrier Couples PGD Cases Initiated ALPORT SYNDROME : COL4A4 1 0 CARNITINE PALMITOILTRANSFERASE II 1 0 GLYCOSILATION DEFICIENCY: TYPE 1A, PMM2 1 1 CYSTIC FIBROSIS 6 3 GAUCHER 1 0 MEDITERRANEAN FEVER 2 1 MIOPATHY ON INCLUSION BODIES: TYPE NIEMANN-PICK : TYPE A 1 1 NON SYNDROMIC DEAFNESS RELATED TO GJB2 7 1 SICKLE CELL DISEASE 4 1 SPINAL MUSCULAR ATROPHY: SMN1 3 2 TAY-SACHS 1 1 Total *Kumar, N., Bisignano, A., Asgari, S., Chu, B., Munne, S., Grifo, J., Berkeley, A., Licciardi, F., Chen, S., Hoffman, D., Barrionuevo, M., Prates, R. October From Carrier Screening to Single Gene PGD: An Analysis of 1/479 Couples Screened via an Expanded Carrier Screening Platform. ASRM 2014.

42 Couple Report

43 FOR OOCYTE DONATION

44 DONOR TESTS OLD PARADIGM we have healthy donors Only few diseases Some characterisecs selected by phenotype NEW PARADIGM Test donors and couples for as much diseases as possible Don t rule out affected donors (40%) but avoid matching (2.4%)

45 Validation Phase

46 Validation Phase Recombine FertilityMap The unique test based on the Genetics of Infertility Designed to provided to patients and doctors the best options for a success pregnancy 1 test. 30+ causes of infertility 70+ genes variants.

47 Dr. Howard Jones (July 31st 2015) Thank you Dr. Jones!

48 Thank you for your attention Teşekkürler