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Arginemia (ARG)

• Born normal but genetic screening show arginemia

  • Rare autosomal recessive condition caused by deficiency of the enzyme arginase which breaks down arginine

• Result:

  • Ammonia build up in infants

  • Poor growth, muscle control

  • Learning delays

• Treatment:

  • Low protein diet

  • Medication clearing ammonia from blood

  • Regular blood testing

• Parents were heterozygous carriers

  • 25% chance of children inheriting it

• Located on: 6q23.2 (chromosome 6, long arm, region 23.2)

Medical Genetics

• Aims to diagnose and manage medical, psychological, and social aspects of hereditary disease

• A collaborative field between physicians, diagnostic technicians, lab researchers, genetic counsellors

• Primary goals:

  1. Diagnose hereditary conditions in infants

  1. Provide treatments and care for infants with rare inherited conditions

  2. Gather info from the patient and family to address whether future children are at risk of being born with condition

Hereditary Disease

• Goal of a medical geneticist to diagnose which category a disease phenotype falls into

1. Mendelian conditions – predictable

   1. Autosomal dominant = Huntington's

   2. Autosomal recessive = most

   3. X-linked dominant = hypertrichosis

   4. X-linked recessive = hemophilia

2. Chromosomal conditions – meiosis

   1. Non-disjunctions

   2. Chromosomal translocations

   3. Chromosomal inversions

3. Multifactorial conditions – epigenetics

   1. Influence of multiple genes and environmental factors

   2. Diabetes, heart disease, cancer

Tools of a Medical Geneticist

• Online Mendelian Inheritance of Man (OMIM)

  • Open source database for anyone to access

  • Catalogues genetic info for human phenotypes, including diseases

  • Quick facts and references to primary literature

    • What the disease is

    • Clinical features

    • Location on chromosome

  • Also non-disease phenotypes

    • Researching genes that have been identified in traits known to vary in humans

      • Chromosomal location

      • Gene function

      • Documented mutations

      • Phenotypes

    • Cytogenetic location = region associated with differences in these traits

Pedigree Analysis

• Physicians may refer to a genetic counsellor if they suspect a genetic disorder runs in their families

• Can be informative to couples starting a family

Genetic Screening

1. NEWBORN

   • Standard protocol in many countries

   • "heel-prick" taking a blood sample

   • Blood sample checks the baby's physiology AND genetic screen

     • i.e. blood test for nutrients and genetic disease

   • Often involves a metabolic disorder

   • Phenylketonuria was the condition that lead to the development of the first newborn screening

Phenylketonuria (PKU)

• Autosomal RECESSIVE

• Absence of enzyme phenylalanine hydroxylase

  • Converts phenylalanine (Phe) to tyrosine

• PKU results from buildup of Phe

  • Toxic to nervous system

• Children appear normal at birth

• Symptoms start a few months after birth

  • Severe mental and developmental impairment

• Treatment:

  • Low protein diet

    • Deprivation of phenylalanine sources

  • Avoid artificial sweeteners – aspartame

    • Byproduct = phenylalanine

• Since 1960s, >50,000 babies born with PKU have been able to live normal lives

1. PRE-NATAL

   • Genotyping a child before they are born

   • Various protocols:

   1. Non-invasive – no risk

      1. Ultrasound

         • Very common

         • Can detect conditions such as Down syndrome

           • See neck webbing

         • Can detect neural defects

           • Examine head and spine of fetus

         • May not always be conclusive

1. Fetal cell sorting

   • Fetal cells may enter into mother's blood circulation in low amounts

   • This process identifies and isolates fetal cells from blood samples taken from mother

   • Some success but requires further development to be more reliable

1. Invasive – risk of harming fetus

   • Last resort, only if non-invasive methods are inconclusive and there are concerns about child inheriting a condition that runs in the family

   • Goal is to extract a sample of stem cells from the amniotic fluid or chorion

   • Cells can be cultured and genetically tested

   • Tests include examining chromosome karyotype, DNA genotyping, etc.

1. Amniocentesis

   • Extract amniotic fluid with a syringe under guidance of an ultrasound

   • Culture fetal cells to examine biochemical, DNA, or chromosomal abnormalities

1. Chorionic villus sampling (CVS)

   • Catheter inserted through vagina and cervix to the chorion under ultrasound guidance

   • Extract small amount of material from chorion

   • Used for biochemical, DNA, or chromosome analysis

Karyotype Analysis

• Can detect chromosomal abnormalities

• Examples:

  1. Robertsonian translocation

     • Chromosomal 21 translocated to chromosome 14

     • If normal chromosome 21 and fused chromosome 21+14 are passed on, and that gamete fertilizes a normal gamete the resulting gamete will have an extra chromosome

(3 chromosome 21s)

1. Down syndrome

   • Trisomy-21

(3 chromosome 21s)

1. Turner syndrome

   • Female missing an X chromosome

(1 X and no Y)

DNA tests – Genetic Markers

• Use genetic markers identified through research linked to disease-causing genes

• Cheap and quick

  1. Variable number Tandem Repeat (VNTR)

     • i.e. larger fragments on gel = more repeats

  2. Restriction Fragment Length Polymorphism (RFLP)

     • i.e. genetic fingerprinting

  3. Single Nucleotide Polymorphism (SNP)

     • Gold-standard

Huntington's Disease

• HD is a genetically inherited neurodegenerative condition

• Autosomal dominant

• Symptoms:

  • Appear between 30-50 years of age

  • Start with subtle problems with mood and mental abilities

  • Can rapidly advance

    • Inability to talk

    • Dementia

    • Depression

    • Immobility

• The HD gene has a variable number of CAG triplet repeats

  • If the length of this repetitive sequence is >34 repeats, the protein product functions abnormally and can result in HD

    • If there are less than 34 CAG repeats, you are fine

    • If there are more than 34 CAG repeats, you get HD

  • Can be diagnosed by amplifying repeat region via PCR and analyzing size of the DNA amplicon on an agarose gel

    • Agarose gel PCR

    • Primers flank CAG repeat regions

    • Amplify the genomic region

    • Diagnose them as having HD or not

    • Longer fragments shown in lanes 2-9 show high risk of HD (i.e. 200bp)

    • Shorter fragments are unaffected  (i.e. 75 bp)

• Ethical struggles:

  • Double-edged sword of genetic testing

  • If you are a carrier, do you want to get your child tested before birth?

  • Would you treat child differently?

  • If your parent had it, would you want to know if you also inherited it?

Genetics, Society, Ethics

• Eugenics: "enhancing humanity" by either encouraging select individuals to have children or discouraging select people against having children

  • Promoted by increased genetic screening and engineering

• If genetic data becomes more accessible to government or corporate agencies:

  • Healthcare may be denied

  • Insurance may increase for those at risk

  • Employment may be denied

• Examples:

  • Iceland diagnosed Down syndrome pregnancies are aborted after prenatal testing

  • Chinese doctor genetically edited twins

  • 23andMe selling genetic data

POSITIVES:

• Newborn screening identifies rare diseases that can be treated and allow diagnosed children to live normal lives

• Knowledge may empower people to improve their lifestyle to minimize risks of disease

• Genetic tests can reconnect long-lost relative

• Increased innovations and knowledge could = better cancer therapies