Chapter 6 – Pedigree Analysis and Applications

Pedigree• Visual representation of family tree with history

of studied trait– Proband – person originally studied

• Oldest generation at the top; youngest generation at the bottom– Roman numerals used for generations (I being the

oldest)

• Numbered from left to right within a single generation

Autosomal recessive traits

• Trait seen in roughly equal amounts of males and females

• Seem to skip generations– Affected individual can

have unaffected parents

Autosomal dominant

• Equal frequency of males and females

• No skipping of generations

• All affected individuals have an affected parent

• (affected individuals tend to be heterozygous)– Some traits are lethal in

homozygous form• Achondroplasia

X linked recessive

• Affected phenotype seen more commonly in males

• Tend to skip generations

• Affected males do not pass trait to sons

X linked dominant• Do not skip generations

• Seen in both males and females

• Females may be more numerous – Females can get disease

from either parent while males can only get from mother

• Affected male will have 100% daughters affected

Y linked

• Only males affected

• Affected males will have 100% affected sons

• Do not skip generations

Twin studies

• Dizygotic – Non-identical twins; fraternal – 2 separate eggs fertilized– 50% average relatedness; same as any sibling

pair

• Monozygotic– Identical – One zygote that splits very early in embryonic

development

Concordance studies• % of twin pairs that have the same trait

• Monozygotic twins are 100% genetically identical; dizygotic approx 50%

• Used to evaluate genetic vs environmental factors

• Genetic influenced traits will show higher concordance in monozygotic twins

Adoption studies• Examines effects of genes (biological

parental traits) vs environment (adoptive parental traits)

• Adoption parents have 0% relatedness to adopted child, but share same environment

• Adoptees tend to resemble biological parents (obesity, alcoholism)

Genetic counseling• Provide education regarding genetic diseases –

risks, testing options– Provides NON-DIRECTIONAL information– Informed consent

• Reasons for seeing a genetic counselor– Positive family history– Advanced maternal age– Abnormal prenatal test results– Infertility– Ethnic background

Prenatal testing • Ultrasound

– Can be performed as early as several weeks after fertilization

– Noninvasive

– Gives image of fetus• Anatomical

abnormalities, neural tube defects, nuchal translucency, amount of amniotic fluid, fetal size

Prenatal testing • Amniocentesis

– 15-18 weeks

– Trans-abdominally or trans-vaginally, depending on placental location

– Ultrasound guided

– Needle inserted and ~15ml of fluid extracted

• Fluid can be tested directly (biochemical) or fetal cells cultured prior to testing (biochemical, molecular, cytogenetics)

• Each ml of fluid contains only ~10-15 cells

Prenatal testing• Chorionic villi sampling

(CVS)– Ultrasound guided

– Small section of chorion is suctioned off (10-15mg)

– Large number of fetal cells reduces time/need for culturing

– Increased risk for limb reduction of performed at earlier gestation

• Eliminates proper blood supply to developing limb

Prenatal testing• Fetal cell sorting – in development

– Isolation of fetal cells from maternal bloodstream

– Minimally invasive

• Pre-implantation – IVF procedure– One cell is removed from 8-16 cell embryo

and tested• Only “healthy” embryos are implanted

Postnatal testing

• Newborn screening – Panel varies from state to state

• Heterozygote/carrier testing– Positive family history or particular ethnic

background– Biochemical or molecular testing

• Depends on specific disease involved

Postnatal testing

• Pre-symptomatic testing– Inherited cancer alleles – increased risk for cancer– Late-onset diseases

• Huntington disease

• Chromosome analysis/cytogenetic testing– Diagnostic and prognostic value in cancer– Infertility – Child with structural chromosomal abnormality

• Inherited or de novo mutation