Genetic Disorders: Autosomal Inheritance

• Genetic disorders stem from mutations in a single gene of an allelic pair, producing different phenotypic effects, and are categorized by their inheritance patterns.

Autosomal Dominant Inheritance

• Traits appear equally in both sexes and require at least one parent to have the trait unless a new mutation occurs.
• If a homozygous individual with the trait mates with a normal individual, all offspring will carry the trait.
• If a heterozygous individual mates with a normal individual, there's a 50% chance each offspring will show the trait.
• Most individuals showing a rare autosomal dominant trait are heterozygous.

Autosomal Recessive Inheritance

• The mutant gene does not produce a new characteristic in the heterozygous state.
• The characteristic occurs with equal frequency in both sexes.
• Both parents must be carriers for the characteristic to be present in offspring.
• If both parents are homozygous for the recessive trait, all offspring will have it.
• If both parents are heterozygous, there's a 25% chance offspring will have the trait.
• Pedigrees with frequent occurrences of rare recessive characteristics often show consanguinity.

X-Linked Recessive Inheritance

• Mutation on the X chromosome is unable to produce a change in phenotype.
• The condition is more common in males.
• If both parents are normal but produce an affected male, the mother is assumed to be a carrier.
• For an affected male to be produced when the father is affected, the mother must be heterozygous for the trait.
• Females with the trait can inherit a recessive gene from both parents or express it due to the Lyon hypothesis.
• All females are mosaics for their functioning X chromosome.

X-Linked Dominant Inheritance

• The mutation produces a protein that presents in the heterozygous state.
• The characteristic occurs at the same frequency in males and females.
• An affected male mated to a normal female will pass the characteristic to 50% of offspring.
• An affected homozygous female mated to a normal male will pass the characteristic to all offspring.
• Heterozygous females may not always show the dominant trait due to the Lyon hypothesis.

Applications of Mendelian Laws

• Carriers of recessive characteristics can be identified because they possess 50% of the protein that the gene is responsible for producing.

Polygenic Inheritance

• A single phenotypic feature is inherited as a result of the effects of many genes.
• Most physical features are determined by polygenic inheritance.
• Common malformations include cleft palate with or without cleft lip, clubfoot, anencephaly, dislocation of the hip, and pyloric stenosis.

Epigenetics

• Epigenetics involves the regulation of gene expression, not encoded in the gene sequence, but through processes like genomic imprinting.

Genomic Imprinting

• There is differential expression of maternal and paternal genomes.

Cytogenetics

• Cytogenetics involves the identification and study of chromosomes.

Identification of Chromosomes

• Chromosomes are identified and numbered in decreasing order from 1-22, with sex chromosomes designated as X and Y.
• Q banding involves staining fixed chromosome spreads without pretreatment.
• G banding involves incubating preparations in saline solutions.
• R banding involves incubating preparations in buffer solutions at high temperatures or specific pH levels.
• C banding involves heating preparations in saline below boiling or treating with alkali solutions.

Cell Division

• Cell division is studied at the beginning of the cell cycle which includes G1, S, G2, and M stages.
• The length of the G1 phase depends on how rapidly the cell is multiplying.
• The S stage is the period of DNA synthesis.
• G2 is when DNA synthesis is complete, and chromosome replication starts.
• The M stage is where cell division occurs.
• Mitosis is the somatic division of cells, divided into prophase, metaphase, anaphase, and telophase.
• Prophase: chromosomes shorten, thicken, and become visible as two long strands.
• Metaphase: spindle forms and chromosomes line up.
• Anaphase: centromere divides, and daughter chromatids move to opposite poles.
• Telophase: spindle breaks, cytoplasm divides, resulting in two diploid cells with 46 chromosomes each.

Abnormalities in Chromosome Morphology and Number

• An example trisomy is where the morphology isn’t affected but the number of chromosomes is.

Methods of Study

• Sex Chromatin (X-Chromatin) Body (Barr Body)
• First seen in a female cat.
• A constricted non-functioning X chromosome is seen.
• Drumsticks are small outpouchings of nuclei lobes in female polymorphonuclear leukocytes.
• Chromosome counts are usually performed on 20-50 chromosome spreads to determine mosaicism.
• Banding techniques are used to identify chromosomes in the karyotype with certainty.

Applied Genetics

• Chromosomes & Spontaneous Abortion
• Investigations started in the early 1960s and showed showed that early abortions are often due to chromosome abnormality.
• Abortions in the first 8 weeks have a higher chance of being related to chromosomal issues.

Recurrent Pregnancy Loss

• Defined as 2 or more SABs (spontaneous abortions).

Chromosomal Disorders

• The 3 most common trisomies are 13, 18, and 21.
• Down syndrome can result from translocation with 15/21, 21/21, or 21/22.
• Down syndrome is the most common chromosomal disorder.

Prenatal Diagnosis

• AFP (Alpha-Fetoprotein) was the first to be studied and tested for in OBGYN.
• AFP is drawn between 16-18 weeks and correlated with increased incidence of NTD (neural tube defect).
• Now assess for T13, T18 & T21.
• Also looks for CF, Sickle cell disease, and Huntington’s disease

Neural Tube Diseases (anencephaly, spina bifida, meningomyelocele)

• Chromosome Abnormalities
• T21 (Downs) presents with low AFP but high HCG.
• T18 presents with low AFP & HCG.

Cystic Fibrosis

• Testing is recommended if there is a family history of CF or a higher frequency of CF in the population.
• Fetal testing should be done if both partners are carriers.

Current Recommendations in Prenatal Screening

• Includes first and second trimester screening, and cell-free fetal DNA testing.

First Trimester Screening

• US & serum analyte combined between 10-13.6 weeks, requiring crown rump length between 38-84mm.
• Ultrasound measures nuchal translucency.
• Plasma protein and HCG results from the US give an estimate of T13, 18, 21.
• Positive results should prompt genetic testing and cell-free fetal DNA, CVS, or amniocentesis.

Second Trimester Screening

• Performed 15-22.6 weeks.
• Uses a quad screen.

Cell-Free Fetal DNA Testing

• Evaluates short segments of fetal DNA present in maternal blood from placental cells.
• Screens for fetal sex, RH status, and some autosomal dominant genetic diseases.
• Can be done as early as 10 weeks with 98% sensitivity in detecting T21.
• Does not detect NTDs.

Fetal Karyotyping

• Methods of include Amniocentesis and Chronic Villus Sampling

Amniocentesis

• Prenatal diagnosis of genetic diseases for:
  • Maternal age 35 or above
  • Previous chromosomally abnormal child
  • 3 or more SABs
  • Patient or partner with chromosome abnormality
  • Family history of abnormality
  • Possible female carrier of X linked disease
  • Metabolic disease (previous experience or family history)
  • NTD risk (previous experience or family history)
  • Positive 2nd trimester maternal serum screen
• Metabolic diseases can be diagnosed prenatally by amniocentesis, performed between 15-17 weeks.
• Increased risk of miscarriage.

Chronic Villus Sampling (CVS)

• Uses 1st trimester testing for cytogenetic testing.
• Can be performed earlier in pregnancy for earlier pregnancy termination decisions.

Karyotyping & Fluorescence in Situ Hybridization Analysis

• Detects chromosomes 13, 18, 21, 22 and XY sex chromosomes.

Single Gene Defects

• If one parent is affected by an autosomal dominant condition, the chance of the child being affected is 1 in 2.
• If both parents are autosomal recessive carriers, there is a 1:4 chance the child will be affected and a 1:2 chance the child will be a carrier.

Genetic Counseling

• Interaction between physician, family, and genetic counselor determines genetic specific information for each person and possibilities of offspring carrying chromosomes.

Gynecologic Correlates

• The Chromosomal Basis of Sex Determination

Syngamy

• Female XX chromosomes.
• Male XY chromosomes.

Abnormalities of Meiosis and Mitosis

• These can result in abnormal sex chromosome numbers or structures.
• An extra sex chromosome can be present.
• A sex chromosome can be absent.
• Two cell lines can have different sex chromosomes arising by mosaicism/chimerism.
• A structurally abnormal sex chromosome can be present.
• The sex chromosome complement can be inconsistent with the phenotype.

The X Chromosome in Humans

• On day 16 of embryonic life, the X chromatin body (Barr body) appears.
• All females are hemizygous with respect to the X chromosome.
• Examples of X-linked conditions include hemophilia, color blindness, childhood MD (Duchenne’s), and Lesch-Nyhan syndrome.

The Y Chromosome in Humans

• Fewer traits are traced to the Y chromosome except for those related to testicular formation.
• A Y chromosome without an X is apparently lethal.
• Testicular development is determined by the testis-determining factor (TDF); without it, normal female anatomy will develop.

Y Chromosome Microdeletion

• Small parts of the Y chromosome can be deleted, which plays a crucial role in male sex determination and sperm production and can determine fertility.

Abnormal Development

Ovarian Agenesis-Dysgenesis

• Turner’s syndrome involves sexual infantilism, webbing of the neck, and retardation of growth.
  • History of Gonadal Agenesis: abnormal ovaries in patient with gonadal streaks.

Clinical Findings of Ovarian Agenesis-Dysgenesis

• A. Symptoms & Signs
  • 1. In newborn infants, edema of hands and feet, associated with large dilated vascular spaces.
  • 2. In adolescents, shortened stature.
  • Most only have 1 normal X chromosome
• B. Laboratory Findings
  • Elevation in total gonadotropin production.
    • Practical Point: ovarian failure over age 15 is not considered diagnostic.
  • Urinary excretion of estrogen is low.
• Treatment:
  • Substitution therapy with estrogen to develop secondary characteristics.
  • Growth hormone to increase height.
  • Low-dose estrogen replacement therapy starting at 11/12 years old and increasing through puberty.

True Hermaphroditism

• Both ovarian and testicular tissue are demonstrated in one patient.

Clinical Findings of True Hermaphroditism

• A. Symptoms & Signs: No exclusive features clinically.
  • Firm diagnosis is possible after the onset of puberty when clinical features become evident.
  • Diagnosis should be made during infancy. B. Sex Chromosome Complements
  • Most have X chromatin bodies and karyotypes indistinguishable from normal females (46XX, 46XY).

Treatment for True Hermaphroditism

• Surgical removal of contradictory organs is indicated.

Klinefelter’s Syndrome

• Occurs in apparent males

Clinical Findings of Klinefelter’s Syndrome

• A. Symptoms & Signs: Not recognizable before puberty except by routine screening of newborn infants.
• Typically have a normal general appearance.
• B. Laboratory Findings: Excessive pituitary gonadotropin is found in urine or serum assay.
• C. Histologic & Cytogenetic Findings: A form of primary testicular failure.

Treatment for Klinefelter's Syndrome

• No treatment for complaints of infertility and gynecomastia.
• No hormone regimen is effective in treating breast hypertrophy.
• Substitution therapy with testosterone for clinical symptoms of hypoleydigism.
• Donor sperm for infertility support.