carrier sensor - amazon s3 · 2018-09-28 · carrier sensor order number: demo_ml potential mother:...

Carrier SensorJohn Doe

DEMO_ML

COVER LETTER

Dear Mr. Doe,

Your sample for the analysis arrived on 05/02/2018 in the laboratory and was evaluatedaccording to the highest laboratory quality standards (ISO 15189). The results wereevaluated and released by two independent geneticists and molecular biologists. Afterobtaining the results, your personal report was compiled. We hereby transmit theresults to you in the format of your choice.

We would like to thank you for your trust and hope that you are satisfied with ourservice. We are always open for questions and suggestions, please do not hesitate tocontact us. This is the only way we can continuously improve our services.

We hope the analysis meets your expectations.

Kind regards,

Dr. Daniel Wallerstorfer BSc.Laboratory Director

Florian Schneebauer, MSc.Laboratory Manager

Carrier Sensor

Order number:DEMO_ML

Potential Mother:Jane Doe 01/02/1985

Potential Father:John Doe 01/01/1990

This report contains personal medical information that is highlyconfidential. Data protection must be ensured.

DEMO_ML Page 1 of 40

INTRODUCTION

GENETICS

YOUR RESULTS

SCIENCE

ADDITIONAL INFORMATION

Carrier SensorLearn about your carrier status of over 170 hereditary disorders anduse this information for optimal family planning and preparation

INTRODUCTION

What/who is a “carrier”?„Carrier“ designates a person, who carriers a genetic defect that does not cause any (orif so, only very mild) symptoms. The carrier normally is completely healthy, but canpass down the illness to his/her children under certain circumstances. You have decidedon a gene-test package that allows you to determine the carrier-status and allows foroptimal family planning.

Every human has (with a few exceptions) two copies of every gene-type; one from their motherand one from their father. A carrier is someone who carries one functional and onedysfunctional (mutated) version of the same gene. With the illnesses/disorders examined inthis program one correctly functioning gene is sufficient to not show any symptoms of thedisorder and to lead an unimpaired life.

In this case one does not show any symptoms, but it is possible to pass on the dysfunctionalversion of the gene to progeny. 50% of the children will inherit a defective gene of this type.This is no problem in most cases, since typically the child inherits a functional gene from theother parent and only is a carrier without any afflictions, too.

Being a carrier for a disorder is neithermedically problematic nor rare. Studies haveshown that app. 24% of all humans arecarriers for at least one such disorder.

Being a carrier is only problematic when bothparents are carriers for the same disorder. Inthose cases, it is possible for a child to inheritthe defective gene from each parent. Thechild thus has no functional gene to fulfil thenecessary task and will in this case sufferfrom a genetic disorder.

Since a child statistically only inherits twodefective genes from two carrier-parents in25% of all cases, only the disorder actuallyaffects every fourth child. This informationabout a possible carrier status allows forspecific precautions in family planning.

Carrier


ADVANTAGES

Advantages of the Carrier SensorThe Carrier Sensor allows you and your doctor to determine your carrier status andthus calculate the risk of passing on a severe genetic disorder to your children. That iswhy it is recommended to test both parents. This knowledge enables optimalpreparation and family planning.

The Carrier Sensor carried out on you examines over 100 genes associated with 170 hereditarymetabolic disorders. In analysing both parents it is possible to determine the possible risk forhaving a potentially affected child. It is important to understand how the inheritance of thedisorders examined here works.They can be sub-divided in 2 types:

➤ TYP1-disorders (affects men and women)➤ TYP2-disorders (are gender-dependent and affect men more frequently).

On the following pages, you will find a clear, easy to follow explanation of these 2 types ofdisorders. With the help of these images carriers can calculate the risk of passing on a defectivegene to their offspring.

Prevention

If both parents are carriers for the same disorder, there are 3 options of dealing with thisfinding:

➤ Preimplantation genetic diagnosis: With these disorders, genetics show that only some, but not allchildren will inherit the disorder. Preimplantation genetic diagnosis offers the most elaborate, but alsoeffective way to prevent a serious and life-threating disorder. 8-20 eggs are harvested from the mother.In the laboratory, they are fertilized with the father’s sperm. One cell is extracted from every embryo.These are genetically screened, and only embryos chosen that did not inherit the genetic disorder. Ahealthy embryo in then implanted into the uterus like with IVF – and nine months later a healthy baby isborn. In this procedure, only completely healthy embryos are implanted, so with high probability it alsoeradicates the disorder from the family tree. This procedure is only recommended when there is the riskof severe disorders that cannot be treated and that impose a great burden on parents and child. ➤ Prenatal screening: A further option is prenatal screening and diagnosis. In an early stage of thepregnancy, an amniotic fluid sample is taken and genetically analysed. This makes it possible todetermine whether the child will suffer from a severe disorder or whether it is healthy. Should the childbe affected by a very severe and life-threatening metabolic disorder, then there is the option of anabortion (if the deadlines are observed). This procedure is only recommended when there is the risk ofsevere disorders that cannot be treated and that impose a great burden on parents and child. ➤ Immediate corrective treatment: Since many of the disorders analysed here, can be treated well ifdiagnosed early, it is important to be prepared. With many disorders, the point in time for the begin oftreatment is crucial for the success of the treatment. Waiting until birth with the analysis, the existenceof the disorder can quickly be ascertained and if necessary the correct therapy can start. In many cases,the child can lead a normal life if certain precautions and therapeutic measures are observed. Thisprocedure is only recommended when the risk is or highly treatable disorders with normal life-expectancy.


INTRODUCTION

GENETICS

YOUR RESULTS

SCIENCE


GENETICSView a brief overview of the genetic theory and how illnesses arepassed on.

TYP1-disorders (gender-independent)Most disorders and illnesses examined here only break out if a child inherits a dysfunctionalgene of the same type from each parent. In professional terminology, the hereditary form iscalled “autosomal-recessive inheritance” (TYP1 – gender-independent). If the child receives thedefective gene from one and a functional gene from the other parent, then it too will become acarrier without any health afflictions. The offspring’s gender is irrelevant in this case.

Inheritance if only one parent is the carrier:

Father Mother

Gene1 Gene2 Gene1 Gene2

Gene1 Gene2

25%healthy carriers

Gene1 Gene2

25%healthy carriers

Gene1 Gene2

25%healthy

Gene1 Gene2

25%healthy

Inheritance if both parents are carriers:

Father Mother

Gene1 Gene2 Gene1 Gene2

Gene1 Gene2

25%sick

Gene1 Gene2

25%healthy carriers

Gene1 Gene2

25%healthy carriers

Gene1 Gene2

25%healthy


TYP2-disorders (gender-dependent)In a small number of the examined disorders inheritance is gender-dependent. Women havetwo copies of a certain type of chromosome (X-chromosome), while men have only one X-chromosome. If a gene defect occurs, a second functional gene of the same type mostly canfulfil the missing function, thus women mostly are only carriers when the defective gene islocated on the X-chromosome. The functional gene on the second X-chromosome performs thenecessary task. Since men only have one X-chromosome, there mostly is no second functioninggene to take on the task. That is why men are more commonly afflicted by these disorders. Thisinheritance is called “X-chromosomal-recessive” in professional terminology.

Inheritance if only mother is the carrier:

Father Mother

Gene1X-Chr Y-Chr

Gene1X-Chr

Gene2X-Chr

Gene1 Gene2

25%sick

Gene1 Gene2

25%healthy

Gene1 Gene2

25%healthy carriers

Gene1 Gene2

25%healthy

Result is:Male offspring50% healthy50% affected

Female offspring50% healthy50 % healthy carrier


Inheritance if only father is the carrier:

Father Mother

Gene1X-Chr Y-Chr

Gene1X-Chr

Gene2X-Chr

Gene1 Gene2

25% healthy

Gene1 Gene2

25%healthy carriers

Gene1 Gene2

25% healthy carriers

Gene1 Gene2

25%healthy

Result is:Male offspring100% healthy

Female offspring100% healthy carriers

Inheritance if both parents are carriers:

Father Mother

Gene1X-Chr Y-Chr

Gene1X-Chr

Gene2X-Chr

Gene1 Gene2

25%sick

Gene1 Gene2

25%healthy carriers

Gene1 Gene2

25%sick

Gene1 Gene2

25%healthy

Result is:Male offspring50% healthy50% affected

Female offspring50 % healthy carrier50% affected


INTRODUCTION

GENETICS

YOUR RESULTS

SCIENCE


RESULTFind out whether a genetic disease was detected here

OVERVIEW

Overview of your resultsHere you will find a list of all genes and disorders examined in this tests and your personalanalysis results.

Table explanation:

The parents' results A You are not a carrier of this disease and also cannot pass it on to your child. C You are a carrier of this disease and could pass it on to your child.

Your child's results A Your child will not suffer from this disease and also not be a carrier. A Your child will not suffer from this disease. However, it is possible that

your child will be a carrier. C Caution! It is possible that your child will suffer from this disease. Speak to

your physician regarding these findings and keep this information in mindwhen planning for your family.


Gene Disease Father Mother Child HSD17B10 17-beta-hydroxysteroid dehydrogenase X

deficiency A A = A

ACADSB 2-methylbutyryl-CoA dehydrogenase deficiency A A = A

HADH 3-hydroxyacyl-CoA dehydrogenase deficiency A A = A

MCCC1 3-Methylcrotonyl-CoA carboxylase 1 deficiency(MCC1D)

A A = A

MCCC2 3-Methylcrotonyl-CoA carboxylase 2 deficiency(MCC2D)

A A = A

AUH 3-methylglutaconic aciduria type I (MCGA1) A A = A

OPA3 3-methylglutaconic aciduria, type III A A = A

DNAJC19 3-methylglutaconic aciduria, type V A A = A

ABCD1 Adrenoleukodystrophy A A = A

HBA1 alpha thalassemia A A = A

HBA2 alpha thalassemia A A = A

ACAT1 Alpha-methylacetoacetic aciduria (3-ketothialasedeficiency)

A A = A

ARG1 Argininemia (Arginase Deficiency) A A = A

ASL Arginosuccinic Aciduria A A = A

SLC25A13 Adult-onset citrullinemia Type II A A = A


Gene Disease Father Mother Child GJB2 autosomal dominant deafness Type 3A A A = A

GJB3 autosomal dominant deafness Type IIB A A = A

GJB6 autosomal dominant deafness Type IIIB A A = A

MAT1A Autosomal dominant persistenthypermethioninemia due to methionineadenosyltransferase I/III deficiency

A A = A

GJB3 autosomal recessive deafness A A = A

GJB2 autosomal recessive deafness Type 1A A A = A

GJB6 autosomal recessive deafness Type IB A A = A

SLC26A4 autosomal recessive deafness type IV A A = A

MAT1A autosomal recessive Methionineadenosyltransferase deficiency

A A = A

TAZ Barth syndrome A A = A

GJB2 Bart-Pumphrey syndrome A A = A

HBB Beta thalassemia major A A = A

PTS BH4-deficient Hyperphenylalaninemia A A A = A

GCH1 BH4-deficient Hyperphenylalaninemia B A A = A

QDPR BH4-deficient Hyperphenylalaninemia C A A = A

PCBD1 BH4-deficient Hyperphenylalaninemia D A A = A

BTD Biotinidase deficiency A A = A

RECQL3 Bloom syndrome A A = A

ASPA Canavan disease A A = A

SLC25A20 Carnitine-acylcarnitine translocase (CACT)deficiency

A A = A

MTRR cbl E complementation type homocystinuria-megaloblastic anemia

A A = A

MTR cbl G complementation type homocystinuria-megaloblastic anemia

A A = A

MMAB cblB complement type Vitamin B-12 responsivemethylmalonic aciduria (due to defect insynthesis of adenosylcobalamin)

A A = A

MMADHC cblD complement type homocystinuria (Variant 1) A A = A

MMADHC cblD complement type homocystinuria (Variant 2) A A = A


Gene Disease Father Mother Child MMADHC cblD complement type Methylmalonic aciduria

and homocystinuria (Variant 1) A A = A

ABCD4 cblJ Type Methylmalonic aciduria andhomocystinuria

A A = A

ASS1 Citrullinemia A A = A

GJB6 Clouston type ectodermal dysplasia Type II A A = A

CFTR congenital bilateral absence of the vas deferens(CVAD)

A A = A

ACSF3 combined malonic and methylmalonic aciduria A A = A

CYP21A2 Congenital Adrenal Hyperplasia due to21-hydroxylase deficiency

A A = A

TXNB Congenital Adrenal Hyperplasia due to21-hydroxylase deficiency

A A = A

PAX8 Congenital hypothyroidism due to thyroiddysgenesis or hypoplasia

A A = A

TSHR Congenital nongoitrous hypothyroidism 1 A A = A

TSHB Congenital nongoitrous hypothyroidism 4 A A = A

THRA Congenital nongoitrous hypothyroidism 6 A A = A

CPT2 CPT2 deficiency associated myopathy A A = A

CFTR Cystic fibrosis C C = C GJB3 Digenic deafness GJB2/GJB3 A A = A

GJB6 Digenic GJB2/GJB6 deafness A A = A

DLD Dihydrolipoamide dehydrogenase deficiency A A = A

GCH1 DOPA-responsive dystonia (with or withouthyperphenylalaninemia)

A A = A

GJB3 Erythrokeratodermia variabilis et progressiva A A = A

GLA Fabry disease A A = A

TAZ familial dilated cardiomyopathy A A = A

IKBKAP familial dysautonomia A A = A

TSHR familial gestational hyperthyroidism A A = A

HADH familial hyperinsulinemic hypoglycemia type 4 A A = A

G6PD Favism A A = A


Gene Disease Father Mother Child GALK1 Galactokinase deficiency with cataracts A A = A

GALE Galactose epimerase deficiency A A = A

GALT Galactosemia C A = A

GBA Gaucher disease Type I A A = A

GBA Gaucher disease Type II A A = A

GBA Gaucher disease Type III A A = A

GBA Gaucher disease Type IIIC A A = A

ETFA glutaric acidemia IIA A A = A

ETFB glutaric acidemia IIB A A = A

ETFDH glutaric acidemia IIC A A = A

GCDH Glutaric aciduria Type I A A = A

GNMT Glycine N-methyltransferase deficiency A A = A

G6PC Glycogen storage disease Ia A A = A

GAA Glycogen storage disease II A A = A

HEXA GM2-gangliosidosis A A = A

HPD Hawkinsinuria A A = A

HBA1 Hb Barts A A = A

HBA2 Hb Barts A A = A

HBB Hb C disease (Hb CC) A A = A

HBB Hb C/ Beta0 thalassemia A A = A

HBB Hb C/Beta+ thalassemia A A = A

HBB Hb D disease (Hb DD) A A = A

HBB Hb D/ Beta0 thalassemia A A = A

HBB Hb D/Beta+ thalassemia A A = A

HBB Hb E/ Beta0 thalassemia A A = A


Gene Disease Father Mother Child HBB Hb E/Beta+ thalassemia A A = A

HBB Hb EE A A = A

HBA1 Hb H (3 gene deletion) A A = A

HBA2 Hb H (3 gene deletion) A A = A

HBA1 Hb H/Constant Spring disease A A = A

HBA2 Hb H/Constant Spring disease A A = A

HBB Hb S/ Beta0 thalassemia A A = A

HBB Hb S/Beta + thalassemia A A = A

HBB Hb Variant/ Beta0 thalassemia A A = A

HBB Hb Variant/Beta+ thalassemia A A = A

HBB Hb variants A A = A

G6PD hemolytic anemia due to G6PD deficiency A A = A

CPT1A Hepatic carnitine palmitoyl transferase deficiencyType I

A A = A

CPT2 Hepatic carnitine palmitoyl transferase deficiencyType II

A A = A

HBB hereditary persistence of fetal hemoglobin A A = A

HEXA Hex A pseudodeficiency A A = A

HMGCL HMG-CoA Lyase Deficiency A A = A

HLCS Holocarboxylase synthetase deficiency A A = A

MTHFR Homocystinuria due to MTHFR deficiency A A = A

CBS Homocystinuria, B6-responsive andnonresponsive types

A A = A

CBS hyperhomocysteinemic thrombosis A A = A

AHCY Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

A A = A

GJB2 Hystrix-like ichthyosis with deafness A A = A

ACAD8 Isobutyryl-CoA dehydrogenase deficiency A A = A

IVD isovaleric acidemia A A = A


Gene Disease Father Mother Child GJB2 Keratitis ichthyosis deafness syndrome A A = A

GALC Krabbe disease A A = A

HADHA LCHAD deficiency A A = A

CPT2 lethal neonatal CPT2 deficiency A A = A

MLYCD Malonyl-CoA decarboxylase deficiency A A = A

DBT Maple syrup urine disease type II A A = A

BCKDHA Maple syrup urine disease, type Ia A A = A

BCKDHB Maple syrup urine disease, type Ib A A = A

ACADM MCAD Deficiency A A = A

HSD17B10 Mental retardation X-linked syndromic 10(MRXS10)

A A = A

MMACHC Methylmalonic aciduria and homocystinuria, cblCtype

A A = A

MUT Methylmalonic Aciduria due to Methymalonyl-CoA Mutase deficiency

A A = A

CD320 Methylmalonic aciduria due to transcobalaminreceptor defect

A A = A

MCEE Methylmalonyl-CoA epimerase deficiency A A = A

MCOLN1 Mucolipidosis IV A A = A

IDUA Mucopolysaccharidosis Ih A A = A

IDUA Mucopolysaccharidosis Ih/s A A = A

IDUA Mucopolysaccharidosis Is A A = A

CFTR neonatal hypertrypsinemia A A = A

SLC25A13 Neonatal onset citrullinemia Type II A A = A

SMPD1 Niemann-Pick disease, type A A A = A

SMPD1 Niemann-Pick disease, type B A A = A

NPC1 Niemann-Pick disease, type C1 A A = A

NPC2 Niemann-pick disease, type C2 A A = A

NPC1 Niemann-Pick disease, type D A A = A


Gene Disease Father Mother Child TSHR nonautoimmune hyperthyroidism A A = A

CYP21A2 Non-classic hyperandrogenism due to21-hydroxylase deficiency

A A = A

PAH Non-PKU hyperphenylalaninemia A A = A

OPA3 optic atrophy 3 with cataract A A = A

OTC Ornithine transcarbamylase deficiency A A = A

GJB2 palmoplantar keratoderma with deafness A A = A

ADA partial adenosine deaminase deficiency A A = A

SLC26A4 Pendred syndrome A A = A

GBA perinatal lethal Gaucher disease A A = A

PAH Phenylketonuria A A = A

PCCA propionic acidaemia A A = A

PCCB propionic acidaemia A A = A

ACADS SCAD Deficiency A A = A

ADA severe combined immunodeficiency (SCID) due toadenosine deaminase deficiency (ADAD)

A A = A

HBB sickle cell anemia (S/S) A A = A

HBB sickle cell disease variants A A = A

HBB sickle hemoglobin C disease A A = A

HBB sickle hemoglobin D disease A A = A

HBB sickle hemoglobin E disease A A = A

CPT2 Susceptibility to acute-infection inducedencephalopathy

A A = A

TG Suscptibility to autoimmune thyroid disease TypeIII

A A = A

SLC22A5 systemic primary carnitine deficiency A A = A

HEXA Tay-Sachs disease A A = A

DUOX2 Thryoid dyshormonogenesis 6 A A = A

SLC5A5 Thyroid dyshormonogenesis 1 A A = A


Gene Disease Father Mother Child TPO Thyroid dyshormonogenesis 2A A A = A

TG Thyroid dyshormonogenesis 3 A A = A

THRB Thyroid hormone resistance A A = A

TCN2 Transcobalamin II deficiency A A = A

HADHA Trifunctional protein deficiency A A = A

HADHB Trifunctional protein deficiency A A = A

FAH Tyrosinemia, type I A A = A

TAT Tyrosinemia, type II A A = A

HPD Tyrosinemia, type III A A = A

MMAA Vitamin B-12 responsive methylmalonic aciduriaMMAA

A A = A

ACADVL VLCAD deficiency A A = A

GJB2 Vohwinkel syndrome A A = A

HCFC1 X-linked mental retardation with methylmalonicacidemia and homocysteinemia

A A = A

IL2RG X-linked severe combined immunodeficiency(SCID)

A A = A


THE RESULT

The resultYour samples were tested for carriership of over 170 genetic diseases and the results evaluatedby our geneticists and molecular biologists.

Carrier status:

Genetic defects detectedThe analysis revealed that you or your partner are a carrier of a genetic disease.

Risk analysis for a common child:

RiskSince the detected genetic defects are present in both potential parents, there's an increasedrisk for your potential child. Here is a list of the relevant genes and diseases:

Disease Father Mother = Child Cystic fibrosis C C = C Helpful links: https://ghr.nlm.nih.gov/condition/cystic-fibrosis (leer)

Speak to your physician regarding these findings and keep this information in mind whenplanning for your family.

More detailed information on the detected genetic defects can be found in the lab findings.Please note: This analysis only examined those genetic diseases, which are included in the listfor this product. Other diseases can not be detected by this test.


LABORATORY RESULT

Lab findingsThe following pages contain the technical evaluation of the analysis, which is meant to be readby your physician. The lab findings also contain technical information such as exact definitionsof the detected genetic variations, information regarding the employed analysis method andpersonal data. Furthermore, these findings allow you to show the analysis result toindependent experts in order to have them verified. The findings are generated automaticallyand only available in English.

EXPLANATION: Changes in the genetic code (deviations from the normal "healthy" code) arecalled genetic variations/variants. These may either have no impact on health (often the case)or cause a risk of disease.

The detected variations are assigned to one of three categories:

Carrier Status Findings

This table contains a list of the detected genetic defects, which might not cause any symptomsin you, but can represent a risk for your offspring. This data forms the basis for the evaluationof your results. If no "variants" are indicated, it means that no genetic defects of this categorywere detected.

Variants of unknown significance

This table contains a list of the detected genetic defects, which deviate from the "normal" genesequence, but are not known to relate to any disease. If no "variants" are indicated, it meansthat no genetic defects of this category were detected.

Other findings

This table contains a list of the detected genetic defects, which might in fact have an effect onyour body, yet are of no direct significance to this analysis. If no "variants" are indicated, itmeans that no genetic defects of this category were detected.


CONFIDENTIAL LABORATORY REPORTWARNING! Contains Patient Protected Health Information (PHI) - Confidential and Intended Solely for Referring Physician/BG Client

Client Name:

Parent Name:

BG Sample ID:

Date of Birth:

Gender:

Race/Ethnicity:

Birth Weight (g):

Specimen Type:

Date Spec Collected:

Date Spec Received:

Report Date:

Ordering Physician:

NPI Number:

Ordering Facility:

Test Performed: Adult Carrier Screening

Indication for Test: Targeted Sequencing/variant analysis of genes associated with newborn metabolic conditions.

Test Results: Findings

BG_20151014_2/Page 1WARNING! Contains Patient Protected Health Information (PHI) - Confidential and Intended Solely for Referring Physician/BG Client

Clinically Significant Findings

Gene Variant Interpretation Associated Condition Mode ofInheritance Zygosity

GALT c.508-24G>A (Intronic)Chr9:34648088 Likely Pathogenic Duarte 2 Galactosemia (GALT) Autosomal

Recessive Hetero

GALT c.940A>G (p.Asn314Asp)Chr9:34649442 Likely Pathogenic Duarte 2 Galactosemia (GALT) Autosomal

Recessive Hetero

Variant of Unknown Significance (VOUS) Gene Variant Zygosity PCCB c.1421A>G (p.Lys474Arg), Chr3:136047622 Hetero

CYP21A2 c.1481G>A (p.Ser494Asn), Chr6:32008904 Hetero MUT c.205A>G (p.Ile69Val), Chr6:49426975 Hetero

DUOX2 c.4475G>A (p.Arg1492His), Chr15:45386810 Hetero

CFTR c.1521_1523delCTT

(p.Phe508del)Chr7:117199644

Pathogenic Cystic Fibrosis (CF) Autosomal Recessive Hetero



Interpretation Summary:The data provided was generated based on the targeted gene sequencing performed: 99.7% of targeted positions were covered with a depth of 6x or greater with an average depth of coverage across targeted regions of 419.1x. 99.8% of areas with clinically significant variants (CLINSIG value of 4 or 5) were covered with a depth of 6x or greater.

All 92 genes included on the panel were evaluated for evidence of clinically significant mutations. All calls within the targeted region were evaluated for evidence of clinical significance including: scientific literature, allele frequency, and predicted protein change. No other variants beyond those contained within the targeted gene regions were evaluated for clinical significance. The variants listed above were identified as pathogenic, likely pathogenic, or variant of unknown significance (VOUS) base on the most current scientific data available.

Clinically Significant Findings:(GALT-c.508-24G>A) Mutations within the GALT gene have been linked in galactosemia. This intronic mutation has been reported to be identified in cis with alleles linked to Duarte 2. The significance of this mutation is not certain. Related literature: Kozák L, et.al., Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R). Hum Mutat. 2000 Feb;15(2):206., Carney, AE., et.al., Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Human Molecular Genetics, 2009, Vol. 18.

(GALT-c.940A>G) Mutations within the GALT gene have been linked in galactosemia. Galactosemia is a condition that affects how an individual processes galactose. This particular variant may cause phenotypic impairment, especially as a haplotype. When the variant occurs in cis with p.L218L it is referred to as Duarte variant 1 and causes increased enzyme activity. When present in cis with C.-119_-116del and intronic polymorphisms c.378-27G>C, c.507+62G>A, c.508-24G>A it is referred to as Duarte variant 2. Related Literature: Elsas LJ, et al. Functional analysis of the human galactose-1-phosphate uridyltransferase promoter in Duarte and LA variant galactosemia.Mol Genet Metab. 2001 Apr; 72(4): 297-305. Carney AE, et al. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Hum Mol Genet. 2009 May 1; 18(9): 1624-32. Reichardt JK, Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2633-7.

Variants Of Unknown Significance (VOUS):VOUS variants are not represented below if associated literature was not identified.




Recommendations:Two heterozygous GALT mutations were identified that have been clinically linked to Duarte 2 Galactosemia. Our lab recommends providing the results to a medical provider or genetic counselor for use during family planning.

TEST METHOD: Submitted specimen genomic DNA was extracted and used as input to a Next Generation Sequencing (NGS) assay on specific exonic regions +/- 25bp into the flanking intronic region (see below) using the Illumina MiSeq sequencing system with 2x150 bp paired-end reads. The DNA sequence was mapped to, and analyzed in comparison with, the published human genome build UCSC hg19 reference sequence. The targeted coding exons were assessed for average depth of coverage and data quality scores. All sequence variants were evaluated using current scientific data to identify pathogenic and likely pathogenic variants. Benign and likely benign variants identified and classified using the latest published, scientific data are not listed on this report. Variants of unknown significance that are either synonymous or outside coding regions are classified as likely benign. This test was developed and its performance characteristics validated by the laboratory.

LIMITATIONS: The lab sequences and analyzes the coding regions and approximately 25bp into the flanking introns of the target gene list. Due to inherent limitations in the testing system, there is a risk of false-negative or false-positive results. Some types of genetic abnormalities, such as copy number changes, may not be detectable with the technologies used by this assay. Only variants categorized as pathogenic, likely pathogenic or non-synonymous with uncertain significance, are indicated on the client report.

ADDITIONAL INFORMATION: Supplementary information on variants can be found here: http://www.babygenes.net/genes-diseases-references OR http://www.ncbi.nlm.nih.gov/clinvar

NEWBORN SCREENING PANEL: The targeted genes have been clinically linked to conditionsidentified in the American College of Medical Genetics (ACMG) recommended Uniform Screening Panel. Exonic coding regions of the following genes are targeted:

ABCD1, ACAD8, ACADM, ACADS, ACADSB, ACADVL, ACAT1, ADA, AHCY, ARG1, ASL, ASS1, AUH, BCKDHA, BCKDHB, BTD, CBS, CFTR, CPT1A, CPT2, CYP21A2, DBT, DECR1, DLD, DNAJC19, DUOX2, EFTA, EFTB, EFTDH, FAH, G6PD, GAA, GALC, GALE, GALK1, GALT, GBA, GCDH, GCH1, GJB2, GJB3, GJB6, GLA, GNMT, HADH, HADHA, HADHB, HBA1, HBA2, HBB, HLCS, HMGCL, HPD, HSD17B10, IDUA, IL2RG, IVD, MAT1A, MCCC1, MCCC2, MCEE, MLYCD, MMAA, MMAB, MMACHC, MMADHC, MTHFR, MTR, MTRR, MUT, NPC1, NPC2, OPA3, OTC, PAH, PAX8, PCBD1, PCCA, PCCB, PTS, QDPR, SLC22A5, SLC25A13, SLC25A20, SLC5A5, SMPD1, TAT, TAZ, TG,TPO, TSHB, TSHR.




Client Name:

Parent Name:

BG Sample ID:

Date of Birth:

Gender:

Race/Ethnicity:

Birth Weight (g):

Specimen Type:

Date Spec Collected:

Date Spec Received:

Report Date:

Ordering Physician:

NPI Number:

Ordering Facility:

Test Performed: Adult Carrier Screening

Indication for Test: Adult carrier screen for variant identification and family planning.

Test Results: Findings

WARNING! Contains Patient Protected Health Information (PHI) - Confidential and Intended Solely for Referring Physician/BG Client

Clinically Significant Findings

Gene Variant Interpretation Associated Condition Mode of Inheritance Zygosity

CFTR c.1521_1523delCTT

(p.Phe508del)Chr7:117199644

Pathogenic Cystic Fibrosis (CF) Autosomal Recessive Hetero



The data provided was generated based on the targeted gene sequencing performed: 99.60% of targeted positions were covered with a depth of 6x or greater with an average depth of coverage across targeted regions of 218.2x. 99.75% of areas with clinically significant variants (CLINSIG value of 4 or 5) were covered with a depth of 6x or greater. All calls within the targeted region were evaluated for evidence of clinical significance including: scientific literature, allele frequency, and predicted protein change. No other variants beyond those contained within the targeted gene regions were evaluated for clinical significance. The variants listed above were identified as pathogenic, likely pathogenic, or variant of unknown significance (VOUS) base on the most current scientific data available. Most of the conditions screened in this newborn screening panel are autosomal recessive disorders. If a child only inherits one non-working copy of the gene (heterozygous), this implies that he or she is a 'carrier' of the condition. Baby's First Test (2015) - Retrieved from: www.babysfirsttest.org/newborn-screening/carrier-identification.

Interpretation Summary:

Clinically Significant Findings:

(CFTR- de ) Mutations in the CFTR gene have been linked to Cystic Fibrosis . This mutation has been categorized as CF-causing by the Clinical and Function Translation of CFTR (CFTR2) Project. Related iterature: US CF Foundation, John Hopkins University. List of CFTR2 Mutations. 27February2015. Rozen, R., et.al., Cystic fibrosis mutations in North American populations of French ancestry: Analysis of Quebec French-Canadian and Louisiana Acadian families. Am J Hum Genet. 1990 Oct; 47(4): 606–610. Penmatsa, H., et.al, Clinical and Molecular Characterization of S1118F-CFTR. Pediatr Pulmonol. 2009 Oct; 44(10): 1003. Castellani C., et.al., Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96.

Variants Of Unknown Significance (VOUS):

None Identified

VOUS variants are not represented below if associated literature was not identified.




Recommendations:Our lab recommends providing the results to a physician, medical provider, or genetic counselor to aid in family planning. Our lab recommends spousal screening of CFTR for family planning purposes.

TEST METHOD: Submitted specimen genomic DNA was extracted and used as input to a Next Generation Sequencing (NGS) assay on specific exonic regions +/- 25bp into the flanking intronic region (see below) using the Illumina MiSeq sequencing system with 2x150 bp paired-end reads. The DNA sequence was mapped to, and analyzed in comparison with, the published human genome build UCSC hg19 reference sequence. The targeted coding exons were assessed for average depth of coverage and data quality scores. All sequence variants were evaluated using current scientific data to identify pathogenic and likely pathogenic variants. Benign and likely benign variants identified and classified using the latest published, scientific data are not listed on this report. Variants of unknown significance that are either synonymous or outside coding regions are classified as likely benign. This test was developed and its performance characteristics validated by the Laboratory.

NEWBORN SCREENING PANEL: The targeted genes have been clinically linked to conditionsidentified in the American College of Medical Genetics (ACMG) recommended Uniform Screening Panel. Exonic coding regions of the following genes are targeted: ABCD1, ACAD8, ACADM, ACADS, ACADSB, ACADVL, ACAT1, ADA, AHCY, ARG1, ASL, ASS1, AUH, BCKDHA, BCKDHB, BTD, CBS, CFTR, CPT1A, CPT2, CYP21A2, DBT, DECR1, DLD, DNAJC19, DUOX2, EFTA, EFTB, EFTDH, FAH, GAA, GALC, GALE, GALK1, GALT, GBA, GCDH, GCH1, GJB2, GJB3, GJB6, GLA, GNMT, HADH, HADHA, HADHB, HBA1, HBA2, HBB, HLCS, HMGCKM HPD, HSD17B10, IDUA, IL2RG, IVD, MAT1A, MCCC1, MCCC2, MCEE, MLYCD, MMAA, MMAB, MMADHC, MTHFR, MTR, MTRR, MUT, NGLY1, NPC1, NPC2, OPA3, PAH, PAX8, PCBD1, PCCA, PCCB, PTS, QDPR, SLC22A5, SLC25A13, SLC25A20, SLC5A5, TAT, TAZ, TG,TPO, TSHB, TSHR.

LIMITATIONS: Our lab sequences and analyzes the coding regions and approximately 25bp into the flanking introns of the target gene list. Due to inherent limitations in the testing system, there is a risk of false-negative or false-positive results. Some types of genetic abnormalities, such as copy number changes, may not be detectable with the technologies used by this assay. Only variants categorized as pathogenic, likely pathogenic or non-synonymous with uncertain significance, are indicated on the client report.

THIS REPORT WAS REVIEWED AND APPROVED BY:

ADDITIONAL INFORMATION: Supplementary information on variants can be found here: http://www.babygenes.net/genes-diseases-references OR http://www.ncbi.nlm.nih.gov/clinvar


Hannis W. Thompson, M.D. - LABORATORY DIRECTOR


INTRODUCTION

GENETICS

YOUR RESULTS

SCIENCE


SCIENCEThis chapter shows the science behind the test.

REFERENCES

ReferencesAll our analyses and treatment recommendations are scientificallyvalidated. Here are some of the relevant literature references for yourinformation.

➤ Lazarin et al., Expanded carrier screening: A review of early implementation and literature, SeminPerinatol. 2016 Feb;40(1):29-34.➤ American College of Obstetricians and Gynecologists. Committee opinion no. 325: update on carrierscreening for cystic fibrosis. Obstet Gynecol. 2005; 106: 1465–1468➤ American College of Obstetricians and Gynecologists. Practice bulletin no. 78: hemoglobinopathiesin pregnancy. Obstet Gynecol. 2007; 109: 229–237➤ American College of Obstetricians and Gynecologists. Committee opinion no. 442: preconceptionand prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent.Obstet Gynecol. 2009; 14: 950–959➤ Gross et al., Professional practice and guidelines committee. Carrier screening in individuals ofAshkenazi Jewish descent. Genet Med. 2008; 10: 54–56➤ Scott et al., Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewishgenetic diseases. Hum Mutat. 2010; 31: 1240–1250➤ Shao et al., Evaluation of a two-year Jewish genetic disease screening program in Atlanta: insightinto community genetic screening approaches. J Community Genet. 2015;6: 137–145➤ Hoffmann et al., The Ashkenazi Jewish carrier screening panel: evolution, status quo, anddisparities. Prenat Diagn. 2014; 34: 1161–1167➤ Kingsmore et al., Comprehensive carrier screening and molecular diagnostic testing for recessivechildhood diseases. (e4f9877ab8ffa9)PLoS Curr. 2012; 4➤ Srinivasan et al., A universal carrier test for the long tail of Mendelian disease. Reprod BiomedOnline. 2010; 21: 537–551➤ Castellani et al., Cystic fibrosis carrier screening effects on birth prevalence and newbornscreening. Genet Med. 2015➤ Hale J., Newborn screening showing decreasing incidence of cystic fibrosis. N Engl J Med. 2008;358:973–974➤ Watson et al., Cystic fibrosis population carrier screening: 2004 revision of American College ofMedical Genetics mutation panel. Genet Med. 2004; 6: 387–391➤ Haque, Expanded carrier screening of 322,484 individuals: the case for going beyond cystic fibrosis.Eur J Hum Genet. 2015;23: S1➤ Cheschier, ACOG Committee on Practice Bulletins. ACOG practice bulletin. Neural tube defects.Clinical management guidelines for obstetricians–gynecologists. Number 44, July 2003. Int J GynaecolObstet. 2003; 83: 123–133➤ ACOG Committee on Practice Bulletins. ACOG practice bulletin no. 77: screening for fetalchromosomal abnormalities. Obstet Gynecol. 2007; 109: 217–227➤ Wilcken, More on medium-chain acyl-Coenzyme A dehydrogenase deficiency in a neonate. N Engl JMed. 2008; 358: 647➤ Bailey et al., No change in the age of diagnosis for fragile X syndrome: findings from a nationalparent survey. Pediatrics. 2009; 124: 527–533➤ Browning et al., Fetal fatty acid oxidation defects and maternal liver disease in pregnancy. Obstet


Gynecol. 2006; 107: 115–120➤ Grody et al., ACMG position statement on prenatal/preconception expanded carrier screening.Genet Med. 2013; 15: 482–483➤ Edwards et al., Expanded carrier screening in reproductive medicine—points to consider. ObstetGynecol. 2015; 125: 653–662➤ Elias et al., Generic consent for genetic screening. N Engl J Med. 1994; 330: 1611–1613➤ Reeves et al., A. Comparison of informed consent preferences for multiplex genetic carrierscreening among a diverse population. J Genet Counsel. 2015➤ Prior, Professional practice and guidelines committee. Carrier screening for spinal muscularatrophy. Genet Med. 2008; 10: 840–842➤ Henneman et al., Responsible implementation of expanded carrier screening: Summary andrecommendations of the European Society of Human Genetics. Eur J Hum Genet. 2015;➤ Klugman et al., Detection of carriers in the Ashkenazi Jewish population: an objective comparisonof high-throughput genotyping versus gene-by-gene testing. Genet Test Mol Biomarkers. 2013; 17:763–767➤ Bell et al., Carrier testing for severe childhood recessive diseases by next-generation sequencing.Sci Transl Med. 2011; 3: 65ra4➤ Lazarin et al., An empirical estimate of carrier frequencies for 400+ causal Mendelian variants:results from an ethnically diverse clinical sample of 23,453 individuals.Genet Med. 2013; 15: 178–186➤ Hallam et al., Validation for clinical use of, and initial clinical experience with, a novel approach topopulation-based carrier screening using high-throughput, next-generation DNA sequencing. J MolDiagn. 2014; 16: 180–189➤ Lim et al., Targeted mutation screening panels expose systematic population bias in detection ofcystic fibrosis risk. Genet Med. 2015➤ Lazarin et al., Systematic classification of disease severity for evaluation of expanded carrierscreening panels. PLoS One. 2014; 9: e114391➤ Grody et al., The cystic fibrosis mutation “arms race”: when less is more. Genet Med. 2007; 9:739–744➤ Perrault et al., Rigorous approach for selection of optimal variant sets for carrier screening withdemonstration of clinical utility. Mol Genet Genomics Med. 2015; 3: 363–373➤ Ready et al., Knowledge and attitudes regarding expanded genetic carrier screening amongwomen’s healthcare providers. Fert Ster. 2012; 97: 407–413➤ American College of Obstetricians and Gynecologists & American College of MedicalGenetics.Preconception and Prenatal Carrier Screening for Cystic Fibrosis. Clinical and LaboratoryGuidelines. American College of Obstetricians and Gynecologists, Washington, DC; 2001➤ Darcy et al., Cystic fibrosis carrier screening in obstetric clinical practice: knowledge, practices, andbarriers, a decade after publication of screening guidelines.Genet Test Mol Biomarkers. 2011; 15:517–523➤ Lazarin et al., Genetic counselors’ perspectives and practices regarding expanded carrier screeningafter initial clinical availability, Genet Couns. 2015;➤ Benn et al., Obstetricians’ and gynecologists’ practice and opinions of expanded carrier testing andnon-invasive prenatal testing. Prenat Diagn. 2014; 34: 145–152➤ Cho et al., Expanded carrier screening in reproductive healthcare: perspectives from geneticsprofessionals. Hum Reprod. 2013; 28: 1725–1730➤ Holtkamp et al., Do people from the Jewish community prefer ancestry-based or pan-ethnicexpanded carrier screening. Eur J Hum Genet. 2015➤ Ross et al., A re-examination of the use of ethnicity in prenatal carrier testing. Am J Med Genet A.2012; 158A: 19–23➤ Shafer et al., Newborn screening for sickle cell disease: 4 years of experience from California’snewborn screening program. J Pedatr Hematol Oncol. 1996; 18: 36–41➤ U.S. Census Bureau. Statistical Abstract of the United States: 2011, 130th ed. Washington, DC; 2010.➤ Sheskin et al., Jewish Population of the United States. University of Connecticut,Storrs, CT; 2010:78➤ Bley et al., Natural history of infantile (GM2) gangliosidosis.Pediatrics. 2011; 128: e1233–e1241


INTRODUCTION

GENETICS

YOUR RESULTS

SCIENCE


ADDITIONAL INFORMATIONIn this chapter you will receive useful and helpful information

CERTIFICATIONS

CertificationsOur laboratory is one of the most modern and automated laboratories in Europe, and hasnumerous certifications and quality assurance systems that meet international standards oreven exceed them. The various fields of business are certified separately to the higheststandards.

Analysis for Lifestlye-purposes

Certified through analysis in our ISO 15189certified laboratory

Medical interpretation of geneticanalyses

Certified through analysis in our ISO 15189certified laboratory

Scientific release of analysis results

Licensed for medical genetic analyses by theAustrian government

Company and office

Certified through ISO 9001


CUSTOMER SERVICE

Customer ServiceQuestions or comments about our service?

Our customer service team is happy to help with any enquiries, questions or problems. You can contactus in the following ways:

➤ [email protected] ➤ +43 662 42 50 99 11

Our team is looking forward to your call. Customer satisfaction is our first priority. If you are not fullysatisfied with our service, please let us know. We will do our best to help find a satisfactory solution toyour problem.

Contact | ImpressumDNAhealthControl(part of Novogenia Group)Saalachstrasse 925020 SalzburgÖsterreich


TECHNICAL DETAILS

Technical details

AddressMusterstrasse 11234 MusterstadtGERMANY

Established analysis methodsqRT-PCR, DNA sequencing, fragment lengthanalysis, CNV assay, GC-MS, Immunocap ISAC,Cytolisa

Order numberDEMO_ML

Detection rate~>99%

Date of birth01/01/1990

Report generated07/02/2018

Performed analyzesB3CAR

Current versionV512

Ordering companyDNAhealthControl(part of Novogenia Group)Saalachstrasse 925020 SalzburgÖsterreich

Analyzing companyDNA Plus - Zentrum für HumangenetikGeorg Wrede Strasse 1383395 FreilassingDeutschland

Laboratory Director

Dr. Daniel Wallerstorfer Bsc.

Laboratory Manager

Florian Schneebauer, MSc.


NOTES:

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Carrier SensorJohn Doe

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