GENE BY GENE CARRIER SCREENING

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2 GENE BY GENE CARRIER SCREENING GENE BY GENE CARRIER SCREEN Various genetic mutations occur with increased frequencies in various ethnic groups in the United States and around the world. For these mutations, carrier screening campaigns are the essence of preventive healthcare in the field of medical genetics. It is thus highly recommended by the American Congress of Obstetricians and Gynecologists (ACOG), the American College of Medical Genetics (ACMG), and other professional organizations to test at the preconception (i.e. before pregnancy) or prenatal (i.e. during pregnancy) stage for a well-defined list of genetic diseases that would put children at risk for being born with a genetic disease. Gene by Gene Carrier Screen tests for these diseases and much more. Traditionally limited to a relatively small number of founder mutations in specific populations at risk, the emerging field of genomic medicine is revolutionizing common preconception carrier screening practices. The Gene by Gene Carrier Screen v1.1 is an expanded screening test covering over 850 mutations in 261 genes representing a total of 253 inherited disorders (autosomal recessive or X-linked). It is expected that individuals screened by the test will have a 1 in 2 to 1 in 4 (the same is to say 50% to 25%) chance of being a carrier for at least one of the included diseases. The test is made available to the general public only through an approved health care provider. THE PANEL The mutation list comprising the Gene by Gene Carrier Screen test adheres to recommended regulatory agency guidelines, curated databases and peer-reviewed manuscripts. It is relevant pan-ethnically with an enrichment on mutations known to affect the various Jewish populations. All founder mutations currently recommended for the various Jewish communities and many mutations recommended for the general population are screened within Gene by Gene Carrier Screen. In addition, an expanded panel for CFTR mutations (that cause Cystic fibrosis, which is the most common life-limiting autosomal recessive disorder in persons of northern European ancestry) includes all mutations recommended for screening by experts on the subject and augmented by the CFTR2 curated database content. Moreover, our innovative genotyping platform allows for the detection of DMD gene deletions and duplications, known to cause Duchenne muscular dystrophy. Finally, additional mutations reported to cause a broad range of disorders is included. Gene by Gene Carrier Screen also routinely tests for Fragile X syndrome and Spinal muscular atrophy which are conditions recommended to be tested for in all populations, regardless of the ethnic background. Page 2 of 12

3 Gene by Gene Carrier Screen expanded panel tests for 253 genetic diseases Screens for 119 genetic diseases prevalent in the Ashkenazi and non-ashkenazi Jewish populations making it the most comprehensive carrier screening panel in the world for the Jewish population. Screens for mutations recommended for non-jewish populations. Screens for an expanded list of mutations found within the CFTR gene that causes Cystic fibrosis. Screens for exonic deletions and duplications found in the DMD gene causing Duchenne muscular dystrophy and related disorders. Screens for Fragile X syndrome carrier status (offered to women only) using PCR method. Screens for Spinal muscular atrophy (SMA) using MLPA testing method. All conditions tested for follow an autosomal recessive pattern of inheritance except for Duchenne muscular dystrophy, Alport syndrome, Adrenoleukodystrophy, Chronic granulomatous disease (CYBB-related), Wiskott-Aldrich syndrome and Fragile X syndrome which follow an X-linked recessive pattern of inheritance, and Familial hypercholesterolemia which follows a co-dominant pattern of inheritance. OMIM Phenotype/ Disease Name Gene ACOG/ACMG 3-methylglutaconic aciduria, type III OPA3 3-phosphoglycerate dehydrogenase deficiency PHGDH Abetalipoproteinemia MTTP Achromatopsia, type 2 CNGA3 Acyl-CoA dehydrogenase, short-chain, deficiency of ACADS Adams Oliver syndrome EOGT Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency CYP11B1 Adrenocorticotropic hormone deficiency TBX19 Adrenoleukodystrophy ABCD1 Aicardi-Goutieres syndrome, type 5 SAMHD1 Albinism, oculocutaneous, type IA TYR Alport syndrome COL4A5 Argininosuccinic aciduria ASL Arthrogryposis, autism spectrum disorder, and epilepsy SLC35A3 Arthropathy, progressive pseudorheumatoid, of childhood WISP3 Asparagine synthetase deficiency ASNS Aspartylglucosaminuria AGA Ataxia-telangiectasia ATM Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia AIRE Bardet-Biedl syndrome 1 BBS1 Bardet-Biedl syndrome 10 BBS10 Bardet-Biedl syndrome 11 TRIM32 Bardet-Biedl syndrome 2 BBS2 Bardet-Biedl syndrome 3 ARL6 Bardet-Biedl syndrome 4 BBS4 Bartter syndrome, type 3 CLCNKB Bartter syndrome, type 4a BSND Beta-globin-related hemoglobinopathies: HbC, HbD, HbE, HbO variants HBB Biotinidase deficiency BTD Bloom syndrome BLM Page 3 of 12

4 OMIM Phenotype/ Disease Name Gene ACOG/ACMG Brittle cornea syndrome, type 1 ZNF469 Canavan disease ASPA Carbamoylphosphate synthetase I deficiency CPS1 Cardiomyopathy, dilated, 1GG SDHA Carnitine-acylcarnitine translocase deficiency SLC25A20 Carnitine palmitoyltransferase deficiency, hepatic, type IA CPT1A Carnitine palmitoyltransferase deficiency, hepatic, type II CPT2 Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome SNAP29 Cerebrotendinous xanthomatosis CYP27A1 Choreoacanthocytosis VPS13A Chronic granulomatous disease (cytochrome b-negative) CYBA Chronic granulomatous disease (cytochrome b-positive, type 1) NCF1 Chronic granulomatous disease, X-linked CYBB Cockayne syndrome, type A ERCC8 Complement factor H deficiency CFH Complex hereditary spastic paraparesis PLAA Congenital adrenal insufficiency with 46,XY sex reversal CYP11A1 Congenital amegakaryocytic thrombocytopenia MPL Congenital disorder of deglycosylation NGLY1 Congenital disorder of glycosylation, type Ia PMM2 Congenital disorder of glycosylation, type Im DOLK Cornelia de Lange like (Birk Flusser) syndrome FRMD4A Cystic fibrosis CFTR Cystinosis, nephropathic CTNS Deafness, autosomal recessive 12 CDH23 Deafness, autosomal recessive 16 STRC Deafness, autosomal recessive 1A (GJB2-related) GJB2 Deafness, autosomal recessive 1B (GJB6-related) GJB6 Deafness, autosomal recessive 22 OTOA Deafness, autosomal recessive 3 MYO15A Deafness, autosomal recessive 59 DFNB59 Deafness, autosomal recessive 7 TMC1 Deafness, autosomal recessive 76 SYNE4 Deafness, autosomal recessive 77 LOXHD1 Deafness, autosomal recessive 8/10 TMPRSS3 Desmosterolosis DHCR24 Diabetes insipidus, nephrogenic AQP2 Diaphanospondylodysostosis BMPER Dihydrolipoamide dehydrogenase deficiency DLD Duchenne muscular dystrophy DMD Dysautonomia, familial IKBKAP Dyserythropoietic anemia, congenital, type Ia CDAN1 Dyserythropoietic anemia, type 2 SEC23B Dyskeratosis congenita, autosomal recessive 4 (TERT-related) TERT Dyskeratosis congenita, autosomal recessive 5 (RTEL1-related) RTEL1 Page 4 of 12

5 OMIM Phenotype/ Disease Name Gene ACOG/ACMG Ehlers-Danlos syndrome, type VII-C ADAMTS2 Enhanced S-cone syndrome NR2E3 Epidermolysis bullosa, junctional, Herlitz type (LAMA3-related) LAMA3 Epidermolysis bullosa, junctional, Herlitz type (LAMB3-related) LAMB3 Epidermolysis bullosa, junctional, Herlitz type (LAMC2-related) LAMC2 Epidermolysis bullosa, junctional, with pyloric atresia ITGB4 Epilepsy, progressive myoclonic 1B PRICKLE1 Factor V and factor VIII combined deficiency LMAN1 Factor VII deficiency F7 Factor XI deficiency F11 Familial hypercholesterolemia (LDLR-related) LDLR Familial Mediterranean fever MEFV Fanconi anemia, complementation group A FANCA Fanconi anemia, complementation group C FANCC Fanconi-Bickel syndrome SLC2A2 Fundus albipunctatus RDH5 Galactosemia GALT Gaucher disease, type I GBA Glanzmann thrombasthenia (ITGA2B-related) ITGA2B Glanzmann thrombasthenia (ITGB3-related) ITGB3 Glaucoma 3A, primary open angle, congenital, juvenile, or adult onset CYP1B1 Glutaric acidemia IIC ETFDH Glutaric aciduria, type I GCDH Glycine encephalopathy (AMT-related) AMT Glycine encephalopathy (GLDC-related) GLDC Glycogen storage disease Ia (von Gierke disease) G6PC Glycogen storage disease Ib SLC37A4/G6PT Glycogen storage disease II (Pompe disease) GAA Glycogen storage disease III (Cori or Forbes disease) AGL Glycogen storage disease IV (Adult polyglucosan body neuropathy) GBE1 Glycogen storage disease V (McArdle disease) PYGM Glycogen storage disease VII (Tarui disease) PFKM Gray platelet syndrome NBEAL2 Growth hormone deficiency, isolated, type IB (GH1-related) GH1 Growth hormone deficiency, isolated, type IB (GHRHR-related) GHRHR Growth retardation, developmental delay, facial dysmorphism (GDFD) FTO Haim-Munk syndrome CTSC Hemoglobin H disease, nondeletional (Hb Constant Spring variant) HBA2 Hemolytic anemia (with or without immune-mediated polyneuropathy) CD59 Hereditary spastic paraparesis, type 49 TECPR2 Hermansky-Pudlak syndrome 3 HPS3 Hermansky-Pudlak syndrome 6 HPS6 This condition follows a co-dominant pattern of inheritance. This means that carriers maybe symptomatic in adulthood and may require treatment. Individuals that are homozygous affected present with severe symptoms in childhood and have a limited life expectancy. Testing for this condition is optional. Page 5 of 12

6 OMIM Phenotype/ Disease Name Gene ACOG/ACMG HMG-CoA lyase deficiency HMGCL Homocystinuria due to MTHFR deficiency MTHFR Hyperinsulinemic hypoglycemia, familial, 1 ABCC8 Hyperoxaluria, primary, type 1 AGXT Hyperoxaluria, primary, type III HOGA1 Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis SARS2 Hypoaldosteronism, congenital, due to CMO II deficiency CYP11B2 Hypomagnesemia 1, intestinal TRPM6 Hypoparathyroidism-retardation-dysmorphism syndrome TBCE Hypophosphatasia, infantile ALPL Hypophosphatemic rickets with hypercalciuria SLC34A3 Hypothyroidism, congenital, nongoitrous, 1 TSHR Hypotonia-cystinuria syndrome (2p21 deletion syndrome, formerly 2p16 deletion syndrome) Microdeletion Inclusion body myopathy, autosomal recessive GNE Infantile neuroaxonal dystrophy 1 PLA2G6 Insensitivity to pain, congenital SCN9A Insensitivity to pain, congenital, with anhidrosis NTRK1 Isovaleric acidemia IVD Joubert syndrome 2 TMEM216 Kohlschutter-Tonz syndrome ROGDI Krabbe disease GALC Laron dwarfism GHR Leber congenital amaurosis 1 GUCY2D Leber congenital amaurosis 2 RPE65 Leber congenital amaurosis 4 AIPL1 Leber congenital amaurosis 5 LCA5 Leigh syndrome, due to COX deficiency SURF1 Lethal congenital contractural syndrome 2 ERBB3 Lethal congenital contractural syndrome 3 PIP5K1C Lethal congenital contracture syndrome 4 MYBPC1 Leukodystrophy, hypomyelinating, 3 AIMP1 Leukodystrophy, hypomyelinating, 4 HSPD1 Liver failure, transient infantile TRMU Mandibuloacral dysplasia LMNA Maple syrup urine disease, type Ia BCKDHA Maple syrup urine disease, type Ib BCKDHB Maple syrup urine disease, type II DBT Meconium ileus, familial GUCY2C Medium-chain acyl-coa dehydrogenase deficiency ACADM Megalencephalic leukoencephalopathy with subcortical cysts MLC1 Megaloblastic anemia-1, Norwegian type AMN Mental retardation, autosomal recessive 3 CC2D1A Metachromatic leukodystrophy ARSA Microcephaly 9, primary, autosomal recessive CEP152 Microcephaly, postnatal progressive, with seizures and brain atrophy MED17 Page 6 of 12

7 OMIM Phenotype/ Disease Name Gene ACOG/ACMG Minicore myopathy with external ophthalmoplegia Mitochondrial complex I deficiency (NDUFA11-related) Mitochondrial complex I deficiency (NDUFAF5-related) Mitochondrial complex I deficiency (NDUFS4-related) Mitochondrial complex I deficiency (NDUFS6-related) Mitochondrial complex III deficiency, nuclear type 4 Mitochondrial DNA depletion syndrome 2 (myopathic type) Mitochondrial DNA depletion syndrome 3 (hepatocerebral type) Mitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria) Mitochondrial myopathy and sideroblastic anemia 1 Molybdenum cofactor deficiency A Mucolipidosis III gamma RYR1 NDUFA11 NDUFAF5 NDUFS4 NDUFS6 UQCRQ TK2 DGUOK SUCLA2 PUS1 MOCS1 Mucolipidosis IV MCOLN1 Mucopolysaccharidosis type IIIA (Sanfilippo A) Mucopolysaccharidosis type Ih (Hurler syndrome) Multiple congenital anomalies-hypotonia-seizures syndrome 1 Multiple sulfatase deficiency Muscular dystrophy, limb-girdle, type 2B Muscular dystrophy, limb-girdle, type 2C Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 Myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency Myoneurogastrointestinal encephalopathy Nemaline myopathy 2, autosomal recessive Nephronophthisis 2, infantile Nephrotic syndrome, type 1 Nephrotic syndrome, type 2 Neuronopathy, distal hereditary motor, type VI Neutropenia, severe congenital 4, autosomal recessive GNPTG SGSH IDUA PIGN SUMF1 DYSF SGCG FKTN FKRP RAPSN TYMP NEB INVS NPHS1 NPHS2 IGHMBP2 Niemann-Pick disease, type A SMPD1 Niemann-Pick disease, type B Niemann-Pick disease, type C1 Omenn syndrome Osteopetrosis, autosomal recessive 1 Osteopetrosis, autosomal recessive 8 Otospondylomegaepiphyseal dysplasia Pendred syndrome Peroxisome biogenesis disorder 1A (Zellweger) Peroxisome biogenesis disorder 4A (Zellweger) Peroxisome biogenesis disorder 5A (Zellweger) Phenylalanine hydroxylase deficiency (including phenylketonuria) Polycystic kidney disease, autosomal recessive Polymicrogyria, bilateral frontoparietal Pontocerebellar hypoplasia, type 1A G6PC3 SMPD1 NPC1 RAG2 TCIRG1 SNX10 COL11A2 SLC26A4 PEX1 PEX6 PEX2 PAH PKHD1 GPR56 / ADGRG1 VRK1 Page 7 of 12

8 OMIM Phenotype/ Disease Name Gene ACOG/ACMG Pontocerebellar hypoplasia, type 2D (Progressive cerebello-cerebral atrophy, type 2D) SEPSECS Pontocerebellar hypoplasia, type 2E VPS53 Primary ciliary dyskinesia-12 (RSPH9-related) RSPH9 Primary ciliary dyskinesia-16 (DNAL1-related) DNAL1 Primary ciliary dyskinesia-9 (DNAI2-related) DNAI2 Prolidase deficiency PEPD Propionic acidemia PCCA Proximal myopathy and ophthalmoplegia MYH2 Pseudocholinesterase deficiency BCHE Pycnodysostosis CTSK Pyridoxamine 5'-phosphate oxidase deficiency PNPO Retinitis pigmentosa 14 TULP1 Retinitis pigmentosa 25 EYS Retinitis pigmentosa 26 CERKL Retinitis pigmentosa 28 FAM161A Retinitis pigmentosa 36 PRCD Retinitis pigmentosa 57 PDE6G Retinitis pigmentosa 59 DHDDS Retinitis pigmentosa 64 C8orf37 Retinitis pigmentosa 12 CRB1 Rickets, vitamin D-resistant, type IIA VDR Sandhoff disease, infantile, juvenile, and adult forms HEXB Severe combined immunodeficiency due to ADA deficiency ADA Severe combined immunodeficiency, B cell-negative RAG1 Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis POC1A Sialic acid storage disorder, infantile SLC17A5 Smith-Lemli-Opitz syndrome DHCR7 Spastic paraplegia 53, autosomal recessive VPS37A Spondylometaepiphyseal dysplasia, short limb-hand type DDR2 Stargardt disease 1/Cone-rod dystrophy 3 ABCA4 Striatonigral degeneration, infantile NUP62 Stuve-Wiedemann syndrome/schwartz-jampel type 2 syndrome LIFR Surfactant metabolism dysfunction, pulmonary, 3 ABCA3 Tay-Sachs disease (Hexosaminidase A deficiency) HEXA Thiamine-responsive megaloblastic anemia syndrome SLC19A2 Tumoral calcinosis, familial, hyperphosphatemic GALNT3 Tumoral calcinosis, familial, normophosphatemic SAMD9 Tyrosinemia, type I FAH Tyrosinemia, type III HPD Usher syndrome, type 1B MYO7A Usher syndrome, type 1C USH1C Usher syndrome, type 1F PCDH15 Usher syndrome, type 2A USH2A Usher syndrome, type 3A CLRN1 Ventricular tachycardia, catecholaminergic polymorphic, 2 CASQ2 Page 8 of 12

9 OMIM Phenotype/ Disease Name Gene ACOG/ACMG Very long-chain acyl-coa dehydrogenase (VLCAD) deficiency ACADVL Wilson disease ATP7B Wiskott-Aldrich syndrome WAS Wolman disease LIPA Woodhouse-Sakati syndrome DCAF17 Xeroderma pigmentosum, group C XPC Xeroderma pigmentosum, group G/Cockayne syndrome ERCC5 Xeroderma pigmentosum, variant type POLH Fragile X syndrome (recommended by ACOG with genetic counseling 1 ) Fragile X syndrome is the most common form of inherited intellectual disability and autism spectrum disorder in males and is also a significant cause of intellectual disability in females. In the beginning of the FMR1 gene, there is a region of repeating DNA bases referred to by the letters CGG. The number of CGG repeats in the FMR1 gene determines if an individual has Fragile X Syndrome or is at risk to have a child with Fragile X Syndrome. Normal up to 44 CGG Repeats "Asymptomatic" Intermediate CGG Repeats CGG Repeats CGG "Asymptomatic" Carrier 200+ Repeats Fragile X Syndrome is caused by a mutation in the FMR1 gene located on the X chromosome. It is, therefore, inherited in an X-linked manner, meaning that it is passed on from mother to children. Fragile X carrier testing is thus usually offered to women because approximately 1 in 130 to 1 in women in the general population is a Fragile X carrier Recommended by ACOG upon patient request with genetic counseling or if there is a family history of Fragile X-related disorders, intellectual disability, autism, or premature ovarian insufficiency. 2. Sometimes carrier females are mildly affected. Lozano R et al. Fragile X spectrum disorders Intractable Rare Dis Res Nov;3(4): Spinal muscular atrophy (recommended by ACMG) Spinal muscular atrophy (SMA) is an autosomal recessive condition caused by a deletion and/or pathogenic mutation of both copies of the SMN1 gene. Carrier testing for SMA is performed in two ways. First, genetic testing to determine the number of SMN1 gene copies present in an individual is carried out. This method can detect approximately 90-94% of SMA carriers: 0 copies of SMN1 gene - individual is affected with the disorder (but disease severity and SMA type cannot be predicted) 1 copy of SMN1 gene - individual is a healthy carrier for the disorder. Being identified as having 2 (or more) copies of SMN1 gene does not eliminate the possibility that an individual is a carrier: All SMN1 gene copies may be on one chromosome and none on the other, or A pathogenic variant not detectable by the current technology may be present. Page 9 of 12

10 The second method of testing is by analysis for a genetic marker (g.27134t>g) that is oftentimes found in people that have 2 copies of SMN1 gene. Individuals that test positive for this genetic marker are much more likely to have two SMN1 gene copies on one chromosome, and no copies of SMN1 on their second chromosome. Such individuals are termed silent carriers or 2+0 carriers referring to one chromosome having 2 copies of SMN1 and the other chromosome having 0 copies of SMN1. Wild-Type: 2 copies of SMN1 Carrier: 1 copy of SMN1 Silent Carrier: 2 copies of SMN1 SMN1 SMN1 SMN1 SMN1 SMN1 TESTING LIMITATION Gene by Gene is a College of American Pathologists (CAP: ) accredited and Clinical Laboratory Improvement Amendments (CLIA: 45D ) certified clinical laboratory qualified to perform high-complexity testing. This test was developed and its performance characteristics determined by Gene by Gene. It has not been cleared or approved by the FDA. Noteworthy, to date, the FDA does not require this test to go through premarket FDA review. There is a possibility that the tested individual is a carrier for additional mutations not screened in this test. Although molecular tests are highly accurate, it is a screening test only and not diagnostic. Rare analytic errors may occur that interfere with reporting. Sources of these errors include sample mix-up, trace contamination, and other technical errors. The presence of additional variants nearby may interfere with mutation detection. Individuals with certain histories or ethnicities may experience better carrier detection with other testing methods, and it is recommended that these options be reviewed with patients by their healthcare provider. For example, in the case of an individual who has a partner that identifies as a carrier of Tay-Sachs, sequencing the HEXA gene or performing hexosaminidase A enzyme analysis may be warranted. Gene by Gene Carrier Screen results must always be interpreted by a medical geneticist, genetic counselor or other qualified clinician in the context of clinical, familial and ancestral data. Genetic counseling is recommended to properly review and explain these results to the tested individual. TURN AROUND TIME Results are reported to the referring provider within 14 business days from the receipt of the specimen. Page 10 of 12

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