Genes mutations and genetic testing
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School of Medicine, Health Sciences and Engineering Susquehanna Township High School Lecture Series  Week 6, September 2013 Clinical Relevance of This Week’s Topic . Genes, Mutations and Genetic Testing. Wen Jie Zhang, MD, PhD. Environmental Factors. Genetic Factors. (Carcinogens).

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Genes mutations and genetic testing

School of Medicine, Health Sciences and Engineering

Susquehanna Township High School

Lecture Series  Week 6, September 2013

Clinical Relevance of This Week’s Topic

Genes, Mutations and Genetic Testing

Wen Jie Zhang, MD, PhD


Carcinogenesis

Environmental Factors

Genetic Factors

(Carcinogens)

(Mutations)

Cancer

Substitutions

Physical

Deletions

Chemical

Insertions

Biological

Translocations

Lifestyle

Carcinogenesis


The human genome

The Human Genome

23 pairs of chromosomes made of 3 billion base pairs

  • Extragenic DNA

  • Repetitive sequences

  • Control regions

  • Spacer DNA between genes

  • Function mostly unknown

~35,000 genes

70%

30%

ASCO


Genes mutations and genetic testing

The chemical structure of

a four-base fragment of

A DNA double helix.


Genes

Genes


Chromosome and gene

Chromosome and Gene


Gene structure transcription and translation

Gene StructureTranscription and Translation


Polymorphism

DNA sequence changes that may or may not alter

protein function (common definition)

Functional protein

Functional protein

Polymorphism


Disease associated mutations alter protein function

Disease-Associated Mutations Alter Protein Function

Functional protein

Nonfunctional or missing protein

ASCO


Common mutations

Common Mutations

  • Substitutions (point mutation)

    In a DNA sequence, a single nucleotide is exchanged for another (A G, C T), leading to missense or nonsense mutation.

  • Insertions (insertion mutation)

    The addition of one or more nucleotide base pairs into a DNA sequence.

  • Deletions (deletion mutation)

    Part of a chromosome or a sequence (base pairs) of DNA is missing from a DNA sequence.


Missense mutation

Missense Mutation

  • Missense Mutation (non-synonymous)

    is a point mutation in which a single nucleotide change (substitution) results in a codon that codes for a different amino acid

    • Example Genetic Disease

      Sickle-cell disease (SCD) or  sickle-cell anemia (SCA) – a hereditary blood disorder, characterized by red blood cells that assume an abnormal, rigid, sickle shape.


A missense mutation

A Missense Mutation


Mutations

Mutations


Missense mutation cont d

Missense Mutation (cont’d)

  • Missense Mutation (non-synonymous)

    is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid

    • Example Genetic Disease

      Sickle-cell disease (SCD) or  sickle-cell anemia (SCA) – a hereditary blood disorder, characterized by red blood cells that assume an abnormal, rigid, sickle shape.


Nonsense mutations

Nonsense Mutations

  • Nonsense mutation

    is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribedmRNA, and in a truncated, incomplete, and usually nonfunctionalprotein product.

    • Example Genetic Disease

      β-Thalassemia– are forms of inherited autosomal recessiveblood disorders that originated in the Mediterranean region. In thalassemia, the disease is caused by the weakening and destruction of red blood cells.


Simple nonsense mutation

Simple Nonsense Mutation


Large insertion mutation

Large Insertion Mutation


Large deletion mutation

Large Deletion Mutation


Chromosomal translocation

Chromosomal Translocation


Genetic testing

Genetic Testing

  • Genetic testing is “the analysis of, chromosomes (DNA), proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypesfor clinical purposes.”

  • There were more than 1,200 clinically applicable genetic tests available.

  • Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue such as semen.


Types of genetic testing

Types of Genetic Testing


Prenatal diagnostic testing

Prenatal Diagnostic Testing

  • Prenatal testing is used to detect changes in a fetus's genes or chromosomes before birth, offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder.

  • Sex determination (discernment)


Cleft lip palate

Cleft Lip/Palate


Newborn s creening test

Newborn Screening Test

  • Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. The routine testing of infants for certain disorders is the most widespread use of genetic testing

  • Millions of babies are tested each year in the United States. 


Carrier testing

Carrier Testing

  • Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder.


Pre implantation genetic diagnosis

Pre-implantation Genetic Diagnosis

  • Genetic testing procedures are performed on human embryos prior to the implantation as part of an in vitro fertilization procedure.


Predictive and p resymptomatic testing

Predictive and Presymptomatic Testing

  • Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no symptoms of the disorder themselves at the time of testing (BRCA1/2).


Brca1 linked hereditary breast and ovarian cancer

92

Breast,

dx 45, d. 89

86

Noncarrier

Ovary, dx 59

d. 62

Breast, dx 59

73

68

71

BRCA1-mutation carrier

Affected with cancer

Breast, dx 36

36

BRCA1-Linked Hereditary Breast and Ovarian Cancer

ASCO


Risk assessment models

Beth

(27)

Diana

(32)

Cindy, 39

Risk Assessment Models

Breast cancer at 69 y

Risk(%)

19

39

7

Model

Gail

Claus

Normal person

First menstrual period: 15 y

Prior biopsy: 0

Atypical hyperplasia: Unknown

First live birth: No birth

Predicted possibility of BRCA1 mutation=8.5% (Couch Model)

ASCO


Brca1

  • Tumor suppressor gene on chromosome 17

  • Autosomal dominant transmission

  • Protein has role in genomic stability

  • >1,200 different mutations reported

Nonsense

Missense

Splice-site

ASCO

Breast Cancer Information Core

BRCA1


Brca2

  • Tumor suppressor gene on chromosome 13

  • Autosomal dominant transmission

  • Protein has role in genomic stability

  • >1,200 different mutations reported

Nonsense

Missense

Splice-site

BRCA2

ASCO

Breast Cancer Information Core


Forensic identity testing

Forensic/Identity Testing

  • Forensic/identity testing uses DNA sequences to identify an individual for legal purposes. 

  • Can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).


Testing for phamacogenomics

Testing for Phamacogenomics

  • A type of genetic testing that determines the influence of genetic variation on drug response.


Chromosome nomenclature banding patterns

ChromosomeNomenclature &Banding Patterns


Tumor suppressor genes

GeneHuman DiseaseFunction

APCColon cancerInteracts with catenins

DCCColon cancerCAM domains

E-cadherinBreast cancerIntracellularly interacts

(CDH1)with catenins

DPC4Pancreatic cancerTGF--related signaling

BRCA1Mammary cancer/DNA damage repair,

Ovarian cancercheckpoint control, apoptosis

BRCA2Mammary cancerDNA damage repair, genomic

stability

ATMAtaxia-telangiectasiaDNA damage response

mutated geneupstream in p53 pathway

P53Mutated in >50%Transcription factor,

tumorscheckpoint control, apoptosis

Tumor Suppressor Genes


Genes mutations and genetic testing

Coda


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