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 Monozygotic 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 Pre-implantation 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 Heterozygote/carrier testing 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