Human Reproduction, Lectures: Clinical Genetics  
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Clinical Genetics

Donna Dizon-Townson, M.D.
Department of OB/GYN
U of U College of Medicine




Take Home Points


  1. To know and understand pertinent areas to cover when eliciting a genetic history from a patient.

  2. To know and understand the different types of genetic abnormalities: chromosomal, single gene defects (Mendelian disorders), multifactorial / polygenic.

  3. To know and understand the indications, advantages, and disadvantages of several prenatal invasive diagnostic procedures.

  4. To be familiar with several molecular techniques used for prenatal diagnosis.



Aneuploid: A haploid gamete or diploid cell lacking the expected number of chromosomes (n or 2n)

Translocation: Following chromosomal breakage, material may be exchanged between two or more chromosomes. When no genetic material is lost, the translocation is balanced. Translocations may be reciprocal or robertsonian (acrocentric chromosomes: chromosomes 13,14,15,21,22).

Single gene: The DNA sequence encoding a single protein.

Mendelian Inheritance: Genetic traits that follow the Mendelian laws of segregation and independent assortment.

Multifactorial / polygenic: A combination of genetic and environmental factors must be invoked for anomalies whose recurrence risks are greater than the general population but less than that expected on the basis of a single recessive or dominant gene (25% and 50% respectively)

Polymerase chain reaction (PCR): Amplification of short sequences (up to 2kb) of DNA without the need for cloning. This method is based on the use of DNA primers that are complementary to sequences on either side of the DNA of interest. Approximately 35 cycles of denaturation (95ÉC), primer annealing (60ÉC), and extension (72ÉC) are then performed.

Genetic amniocentesis: The prenatal diagnostic procedure involving a needle puncture into the amniotic sac and obtaining amniotic fluid which contains cells of fetal origin. These cells can then either be used directly for fetal DNA analysis or cultured for fetal karyotype.

Percutaneous umbilical cord blood sampling (PUBS): The prenatal diagnostic procedure involving a needle puncture into the fetal umbilical blood vessels and obtaining fetal blood. The fetal blood then may be used directly for fetal DNA analysis, cultured for fetal karyotype, a fetal blood count, or assessment of fetal acid base status.



  1. Genetic History-Taking and Genetic Counseling

  2. General Principles

  3. Procedures for Prenatal Diagnosis

  4. Prenatal Diagnostic Techniques Just around the Corner



  1. Genetic History-Taking and Genetic Counseling

    1. American College of Obstetricians and Gynecologists (A.C.O.G.) recommendations. 21.4% of couples will show at least one positive response, with 7.8% requiring formal genetic counseling. Advanced maternal age is the most common indication for further testing.

    2. The genetic history

      1. Inquire about the health status of 1st, 2nd, and 3rd degree relatives.

      2. Record abnormal reproductive outcomes such as repetitive spontaneous miscarriage, stillbirths, and anomalous fetuses.

      3. Record maternal and paternal drug exposure.

      4. Record maternal and paternal ages.

      5. Record maternal and paternal ethnic origins.

    3. Principles and prerequisites of genetic screening
      Screening programs versus case detection programs

      1. Voluntary

      2. One does not expect to detect all affected cases in a given population.

      3. Establishing technical feasibility for screening a given disorder alone does not justify screening.
        1. Capacity to alter clinical management
        2. Cost-effectiveness
        3. Reliable means of assessment
        4. Capacity to handle problems
        5. Specific indications for heterozygote genetic screening

    4. Principles of genetic counseling

      1. Communication

      2. Nondirective

  2. General Principles

    1. Cytogenetics - Numerical Chromosomal Abnormalities

      1. Karyotype

      2. Aneuploidy - lacks the expected number of chromosomes (n or 2n)
        1. Trisomy (2n +1) Meiotic or mitotic nondisjunction
        2. Polysomy - additional sex chromosome (ex: 47XXY)
        3. Monosomy (2n - 1)
        4. Polyploidy - more than two haploid sets of chromosomes
          1. Triploidy - (3n = 69) most common
            Dispermy most common mechanism

    2. Cytogenetics - Structural Chromosomal Abnormalities

      1. Karyotype and chromosomal banding patterns
        1. Types
          1. Deletion
          2. Translocation
            1. Reciprocal
            2. Robertsonian
          3. Inversions
            1. Pericentric - includes the centromere
            2. Paracentric - does not include the centromere
          4. Isochromosomes
          5. Dicentric chromosomes
          6. Ring chromosomes
          7. Duplications
        2. Etiology - Originate after chromosomal breakage which may be caused by radiation, chemicals, or viruses.

    3. Single Gene Defects (Mendelian Disorders)

      1. Eukaryotic gene structure and expression

      2. Mendelian Inheritance
        1. Autosomal dominant inheritance
        2. Autosomal recessive inheritance
        3. X-Linked inheritance

      3. DNA Technology
        1. Polymerase Chain Reaction (PCR)
        2. Restriction fragment length polymorphisms
        3. Allele-specific hybridization (Dot Blots)

      4. Examples of single gene defects
        1. Hemoglobinopathies
          1. Thalassemia - Quantitative variants
          2. Sickle cell anemia - Structural variants
        2. Coagulopathies
          1. Hemophilia A - X-linked defect
          2. Hemophilia B - X-linked defect
        3. Metabolic disorders - autosomal recessive
          1. Phenylketonuria - Deficiency of phenylalanine hydroxylase
          2. Congenital adrenal hyperplasia - Deficiency of 21 hydroxylase
          3. Alpha-1-antitrypsin deficiency
        4. Neurologic disorders
          1. Duchenne muscular dystrophy
          2. Huntington's disease
          3. Neurofibromatosis

    1. Multifactorial / Polygenic Defects

      1. The trait, the incidence of which usually 1 / 1000 live births, usually involves a single organ system or embryologically related organ systems.

      2. The frequency of similarly affected cotwins is higher among monozygotic than dizygotic twins.

      3. Unlike mendelian inheritance, the recurrence risk increases after more than one progeny is affected. The risk rarely approaches the 25% expected for recessive traits or the 50% expected for dominant traits.

      4. The more serious the defect, the higher the recurrence risk. Bilateral cleft palate carries a higher recurrence risk than unilateral cleft palate.

      5. If the trait occurs more frequently among members of one sex, the risk for relatives is higher if the proband (index case) is of the less frequently affected case. Pyloric stenosis occurs more frequently in males; thus, the recurrence risk is higher if the proband is female.

      6. As the degree of relation decreases, the recurrence risks for relatives decreases more rapidly than that observed for autosomal dominant traits.

      Multifactorial / Polygenic Traits

      • Neural tube defects
      • Cleft lip with or without cleft palate
      • Cardiac defects
      • Diaphragmatic hernia
      • omphalocele
      • Renal agenesis
      • Ureteral anomalies
      • Hypospadias
      • Posterior urethral valves
      • Incomplete muellerian fusion
      • Hip dislocation
      • Limb reduction defects
      • Talipes equinovarus (clubfoot)

    2. Teratogens

      1. Fetal warfarin syndrome

      2. Fetal hydantoin syndrome

  3. Procedures For Prenatal Diagnosis

    1. Amniocentesis

      1. Indications - 15 -17 weeks gestation evaluation of genetics

      2. Risks - 1 /200 fetal loss rate

    2. Chorionic villus sampling
      Transcervical vs Transabdominal

      1. Indications - 9 -12 weeks gestation evaluation of fetal genetics

      2. Risks - 0.6 -0.8% fetal loss rate, ?limb reduction defects, 1% confined placental mosaicism, performed prior to MSAFP screening

    3. Percutaneous umbilical blood sampling

      1. Indications - evaluation of fetal genetics, blood count, acid / base status

      2. Risks - 1% fetal loss rate, 5% preterm labor / delivery

    4. Fetoscopy

      1. Indications

      2. Risks - 1-3% fetal loss rate, 5% preterm labor / delivery

    5. Fetal skin sampling

      1. Indications - Dermatologic disorders

      2. Risks - 2 -3% fetal loss rate

    6. Fetal liver sampling

      1. Indications - Metabolic disorders

      2. Risks - 2 -3% fetal loss rate

    7. Fetal muscle sampling

      1. Indications - Becker-Duchenne muscular dystrophy assay for dystrophin

      2. Risks - 2 -3% fetal loss rate

  4. Prenatal Diagnostic Techniques Just Around the Corner

    1. Fluorescent insitu hybridization (FISH)

    2. Isolating and analyzing fetal cells in maternal blood

    3. Stem cell transplantation

    Simpson JL, Golbus MS. Genetics In Obstetrics & Gynecology W.B Saunders Co., Phila., 2nd Edition, 1992.


Take Home Points

  1. the family history, reproductive outcomes, maternal and paternal ages, maternal and paternal ethnic origins, and drug exposures .

  2. Be familiar with common genetic syndromes and teratogens.

  3. There exist a number of prenatal diagnostic procedures, amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, and fetoscopy, that have their indications, advantages, and disadvantages.

  4. Be familiar with advancing molecular technology and its utility in the clinical setting. It is our responsibility as physicians to keep up with rapidly advancing diagnostic techniques. Techniques such as FISH, isolation of fetal cells in maternal circulation, and fetal stem cell transplantation are in our patients near future.