OB Genetics

1
OB Genetics

• Cary Phillips, M.D

2
CREOG OBJECTIVES

• 1. Describe the basic structure and replication
  of DNA
• 2. Describe the processes of mitosis and meiosis
• 3. Describe the clinical significance of
  karyotype abnormalities such as
• a. Trisomy
• b. Monosomy
• c. Deletions
• d. Inversions
• 4. Describe the clinical significance of
  heritable diseases such and cystic fibrosis,
  Tay-Sachs disease and hemophilia

3
DNA

4
Components of DNA

• DNA is a polymer known as a polynucleotide
• Monomer units are nucleotides
• Nucleotide 5-carbon sugar nitrogen containing
  base phosphate group
• DNA contains four different nucleotides which
  only differ in the nitrogenous base
• Nitrogenous bases are classified into 2 groups
• Purines Adenine and Guanine
• Pyrimidines Cytosine and Thymine
• 
  

5
Purines

• Adenine and Guanine
• Purines are the larger of the two bases
• Nine atoms make up the fused rings
• The 5 carbons and 4 nitrogen's are numbers 1-9

6
Pyrimidines

• Cytosine and Thymine
• Six atoms make up the fused rings
• The 4 carbons and 2 nitrogen's are numbered 1-6

7
DNA Backbone

• Alternating backbone of deoxyribose and
  phosphodiester bonds
• Deoxyribose sugars are joined together by
  phosphodiester bonds
• Chain has polarity 5 to 3 from top to bottom
• A,G,C,T bases extend away from chain
• Bases are hydrophobic

8
DNA Double helix

• Two DNA strands form helical spiral
• Strands run in opposite directions
• Within the helix Adenine forms 2 hydrogen bonds
  with Thymine on the opposite strand
• Guanine forms 3 hydrogen bonds with Cytosine on
  the opposite strand

9
DNA Organization

• Human diploid nucleus contains approximately
  3x10(9) base pairs of DNA
• DNA is packed into cells using histones
• DNA wound around a histone nucleosome
• Nucleosomes are packed together into a cylinder
  called a solenoid
• Solenoids are supercoiled and aggregate into
  chromatin
• Chromatin fibers then aggregate into chromosomal
  bands

10
DNA Replication

• Before a cell can divide it must duplicate all
  its DNA
• This duplication process occurs during the S
  phase of the cell cycle
• Any errors in replication represent genetic
  mutations
• DNA replication is semiconservative
• Each strand of original DNA remains intact and
  serves as a template for synthesis of a
  complimentary strand

11
DNA Replication

• Portion of DNA double helix is unwound by
  Helicase
• RNA primase inserts a starter of RNA nucleotides
• DNA polymerase places complementary DNA
  nucleotides at 3 end of RNA primer
• RNA primase attaches more RNA primers in the
  remaining gaps giving shorter Okazaki fragments

12
DNA Replication

• Exonuclease strips away RNA primer and replaces
  it with DNA
• Ligase inserts phosphate into remaining gaps
• Each DNA molecule now has an old and a new strand
• The cell can now proceed to Mitosis and Meiosis

13
Mitosis

• Mitosis is nuclear division plus cytokinesis
• Mitosis produces two identical daughter cells
• Both cell are diploid (n46)
• Stages included prophase, prometaphase,
  metaphase, anaphase, telophase
• Interphase is sometimes included in mitosis but
  is actually G1,S, and G2 of cell cycle (this is
  when the cell is preparing for mitosis)

14
Mitosis

• Prophase- Chromatin in nucleus condenses,
  nucleolus disappears, centrioles begin to move to
  opposite poles, mitotic spindles begin to form
• Prometaphase- nuclear membrane dissolves,
  proteins attach to centrioles making
  kinetochores, mictortibules attach to kinetchores
  and chromosomes begin to move

15
Mitosis

• Metaphase- spindle fibers align chromosomes in
  middle of nucleus
• Anaphase paired chromosomes separate and move
  to opposite ends

16
Mitosis

• Telophase- Chromatids arrive at opposite poles,
  new membranes form around daughter nuclei,
  cytokinesis begins
• Cytokinesis- fiber ring of actin pinches cell
  into two daughter cells each with one nucleus

17
Meiosis

• Consist of meiosis I and II
• Meiosis I chromosomes in a diploid cell (n46)
  regenerate producing four haploid daughter cells
  (n23). This is the step in Meiosis that creates
  genetic diversity
• Prophase of meiosis I is longer than that of
  mitosis and is divided into stages leptotene
  zygotene, pachytene, and diplotene
• Female oogenesis is arrested in the diplotene
  phase of meiosis I until ovulation occurs
• Meiosis II similar to mitosis, chromatids are
  separated producing two haploid daughter cells

18
Meiosis I

• Prophase I homologous pairs of chromosomes (one
  from each parent) form synapses, formation of
  chiasmata caused by genetic recombination becomes
  apparent.
• Prometaphase I nuclear membrane disappears,
  spindle fibers attach and begin to move the
  chromosomes to opposite poles.

19
Meiosis I

• Metaphase I Bivalents (two chromosomes) align at
  metaphase plate, at this point the alignment is
  random, meaning there is a 50/50 chance daughter
  cell will receive either mothers or fathers
  genetic material
• Anaphase I Chiasmata separate, chromosomes
  each with two chromatids move to separated poles,
  each daughter cell is now haploid

20
Meiosis I

• Telophase I- nuclear envelope reforms, cells can
  start meiosis II at this point
• Cytokinesis analogous to mitosis where two
  daughter cells are formed
• Meiosis II similar to mitosis but produces two
  haploid daughter cells

21
Chromosomal Abnormalities

• Chromosomal abnormalities are responsible for 50
  of embryonic death, 5-7 of fetal losses, 6-11
  of stillbirths and neonatal losses, and 0.9 of
  live-born children
• Trisomy- additional chromosome is present 2n1
• Monosomy- a entire chromosome is absent 2n-1
• Deletions- a portion of a chromosome is missing
• Inversions a portion of the chromosome is
  broken and the genetic material is inverted

22
Trisomies

• Usually result from nondisjunction where
  chromosomes line pair up properly but fail to
  separate
• Less common causes are premature separation of
  paired chromosomes and normal meiotic segregation
  in a trisomy parent
• Incidence of Trisomies increase with increasing
  maternal age. Oocytes are arrested in meiosis I
  and aging is thought to break down the chiasmata
  that keep paired chromosomes aligned
• Most common Trisomies include, Trisomy 21,
  Trisomy 18, and Trisomy 13
• Trisomies of sex chromosomes include 47XXX,
  47XXY, 47 XYY

23
Trisomy 13

• Known as Patau syndrome
• Occurs in approximately 1 in 20,000 births
• Common abnormalities include cardiac defects in
  80-90 and holoprosencephaly in 70
• Other abnormalities include microcephaly,
  microphthalmia, cleft lip, cleft palate, abnormal
  ears, omphalocele, PCKs, and radial aplasia
• Strongly suggestive if cutis aplasia (localized
  punched out appearing scalp) and polydactyly are
  present together
• Median survival rate of 3 days
• 90 die in first month
• Surviving infants are severely mentally retarded

24
Trisomy 13
25
Trisomy 18

• Known as Edward syndrome
• Occurs in 1 in 8000 births
• 85 loss rate between 10 weeks and term
• Most dies within first week of life
• 45 die within one year of life
• Fetuses are usually growth restricted (mean
  2340g)
• Almost every organ system can be affected
• 95 have cardiac abnormalities (VSD,ASD,PDA)

26
Trisomy 18

• Features include prominent occiput, malformed
  auricles, short palpebral fissures, small mouth,
  rocker-bottom feet
• Also may have horseshoe kidney, lapping fingers,
  syndactyly, hernias, diastasis, or imperforate
  anus
• Surviving are severely mentally retarded
• These fetuses commonly have heart rate
  abnormalities during labor
• High primary C/S rate for fetal distress

27
Trisomy 18
28
Trisomy 21

• Incidence is 1 in 800-1000 births
• Most common non-lethal trisomy
• 95 due to maternal nondisjunction
• Remaining 5 result from mosaicism or
  translocation
• Affected children have marked hypotonia, tongue
  protrusion, small head, flattened occiput, flat
  nasal bridge, epicanthal folds with up-slanting,
  palpebral fissures, loose skin around neck,
  short, stubby fingers, single palmer crease,
  clinodactyly, and low IQs
• Associated defects include heart defects
  (endocardial cushion), GI atresias, leukemia and
  thyroid disease

29
Trisomy 21
30
Trisomy 21

• 97 of Down syndrome occurs in families with no
  previous history
• Screening test can be used to identify risk of
  Down syndrome
• Screening test have a high false positive rates
• Women with positive screening test should be
  offered a definitive diagnostic tests such a
  amniocentesis or CVS

31
Screening Tests

• Triple Screen Marker- can be performed at 15-20
  weeks but is more accurate at 16-18 weeks.
  Measure maternal levels of hCG, unconjugated
  estriol (E3), and AFP
• Test detects 60 of trisomy 21 in women less than
  35 and 75 in women older than 35
• Test detects 60-75 of trisomy 18
• In addition, some labs are measuring level of
  dimeric inhibin A along with hCG,E3, and AFP
• Trisomy 21- Increase in hCG E3, decrease in AFP
• Trisomy 18- All three are decreased

32
Screening Test

• Ultrasound- looks for structural abnormalities
• Nunchal lucency- occurs in 27-89 of trisomy 21
• Amniocentesis accuracy in diagnosing
  chromosomal abnormalities is 99 with fetal loss
  rate of approximately 5. Traditionally offered
  between 15-20 weeks
• Chorionic Villus Sampling- accuracy in diagnosing
  chromosomal abnormalities is 99 with
  complication rate of 0.6-0.8. Generally
  performed at 10-12 weeks. Advantage over amnio is
  results are available earlier in pregnancy. There
  are a few rare genetic conditions that require
  CVS for diagnosis

33
Other Trisomies

• 47 XXX tall stature, normal pubertal
  development, normal fertility, wide range of
  IQs,.
• 47 XXY (Kleinfelters syndrome)- tall stature, do
  not virilize, require testosterone therapy, more
  likely to be infertile and have gynecomastia,
  wide range in IQs
• 47 XYY- tall stature, have learning disabilities,
  mild increase in depression, hyperactivity, and
  aggressiveness
• For both males and females a decrease in IQ
  occurs with each additional X

34
45X Monsomy

• Autosomal monosomies are lethal
• 45 X (Turners syndrome) is most common aneuploidy
  in SABs and is responsible of 20 of first
  trimester losses
• Prevalence of 1 in 5000 births
• 45X survivors have a high incidence of mosaicism
• Nonlethal 45X most likely due to postzygotic
  mitotic error not materal age related
  nondisjunction
• Maternal X is retained in 80 of cases

35
45X Monosomy

• Features of 45 X include short stature, broad
  chest with widely spaced nipples, congential
  lymphedema with puffy fingers and toes, low
  hairline, webbed posterior neck, cystic hygromas
  and minor bone and cartilage abnormalities
• 30-50 have major cardiac malformations (aortic
  coarctation and bicuspid aortic valve)
• High likelihood of aortic dissection
• Ovarian dysgenesis (streak ovaries) and
  infertility requiring life long hormone
  replacement occurs in over 90
• Usually have normal IQs

36
45X Monosomy
37
Chromosomal Deletions

• Deletions occur when a portion of the chromosome
  is missing
• Most occur during meiosis due to misalignment or
  mismatching during paring of homologous
  chromosomes
• If deletion is identified parents should be
  tested to find out if it is associated with a
  familial translocation that might reoccur
• Deletions can occur in autosomes or sex
  chromosomes

38
Deletions

• Wolf-Hirschhorn syndrome is the deletion of 4p
  (short arm). Features included fetal growth
  restriction, hypotonia, characteristic facial
  appearance, severe mental retardation, and
  posterior midline scalp defects
• Cri du chat syndrome is the deletion of 5p (short
  arm). Features include high pitched cat like cry,
  sever mental retardation, hypotonia, and growth
  restriction

39
Deletions

• Shprintzen syndrome and DiGeorge sequence result
  from the same 22q11.2 microdeletion
• Shprintzen syndrome (velo-cardio-facial syndrome)
  features include cleft palate, velopharyngeal
  incompetence, prominent toes, a long face,
  protruding mandible, cardiac defects, short
  stature and mental retardation
• DiGeorge sequence is characterized by hypo- or
  aplasias of thyroid and parathyroid and aortic
  arch malformations. Features include facies with
  short palpebral fissures, micrognathia with short
  philtrum, ear anomalies. Height and IQ are
  usually normal

40
Deletions

• Deletions of short arm of X results in Turner
  stigmata with gonadal dysgenesis and short
  stature. Most common occurs on Xp11
• Long are of X (Xq13 XQ21) is responsible for
  ovarian maintenance. Deletions of these regions
  (most common Xq13) result in complete ovarian
  failure, primary amenorrhea, and lack of breast
  development

41
Inversions

• Occurs when two breaks happen in the same
  chromosome. No genetic material is lost but the
  rearrangement may alter gene function
• Paracentric inversions occur when the break is in
  one arm and the centromere is not included
• The carrier can either have a normal gamete or
  gametes that are extremely abnormal and
  fertilization can not occur
• Paracentric inversion carriers have a high risk
  of infertility but a low risk of abnormal off
  spring

42
Inversions

• Pericentric inversions occur when breaks are in
  each arm and include the centromere.
• Misalignment occurs during meiosis and there is a
  high probability of abnormal offspring
• Prenatal testing should be offered to families
  with known inversions and families with recurrent
  pregnancy losses

43
Inheritable Disorders

• About 0.4 of the population has a genetic
  abnormality cause by single gene mutation at age
  25.
• About 2 have single gene mutation diagnosed over
  their lifetime
• Autosomal dominant- when only one member of the
  gene pair determines the phenotype. Carrier have
  50 chance of passing on the affected gene
• Autosomal recessive- traits are expressed when
  both copies of the gene function identically to
  determine the phenotype. The recurrence rate for
  a couple who already has a child affected with an
  AR disease is 25

44
Cystic Fibrosis

• Most common genetic disorder in Caucasians
• Autosomal recessive inheritance
• Frequency is 1 in 1500 Caucasian births and 1 in
  1700 African American births
• Caused by one of gt800 point mutations on 7p
• Most common is DF508 mutation
• Mutations affect the chloride channel CFTR
  (cystic fibrosis transmembrane conductance
  receptor regulator)
• Median survival is 30 years

45
Cystic Fibrosis

• Features include infertility, exocrine gland
  dysfunction, chronic bronchitis, respiratory
  tract infections, and ultimately pulmonary
  insufficiency
• Estimated that 4 of CF affected females become
  pregnant each year
• Common problems in pregnancy include Cor
  pulmonale, pancreatic dysfunction (diabetes),
  respiratory failure
• Prognosis for mother and fetus is based on degree
  of lung involvement

46
Tay-Sachs Disease

• Considered a lysosomal storage disease
• Autosomal recessive inheritance
• Results from a mutation on chromosome 15 which
  causes a severe deficiency in hexosamindase A
• Results in accumulation of GM2 ganglioside in
  lysosomes
• Features included motor and mental deterioration,
  motor incoordination, mental obtundation,
  muscular flaccidity, blindness, and dementia
• Death usually occurs by age 2 to 3 years

47
Tay-Sachs Disease

• Prevelent in Ashkenazi Jews
• Other AR diseases prevelent in this society are
  Canavan (aspartoacyclase) and Gauchers
  (cocerebrosidase) diseases
• Carrier rate in Ashkenazi Jew for Tay-Sachs is 1
  in 30, for Canavan is 1 in 40, and for Gauchers
  is 1 in 12-25
• ACOG recommends offer carrier screening to all
  patients of Jewish descent for Tay-Sachs and
  Canavans. Prenatal diagnosis is available
• Gauchers requires molecular analysis because the
  phenotypes range from mild to severe

48
Hemophilia

• Hemophilia A and B are a X-linked recessive
  disease
• Hemophilia A is a severe deficiency in factor
  VIIIC
• Hemophilia B is a severe deficiency in factor IX
• Disease occurs mostly in men but can occur in
  women if they inherit two abnormal X chromosomes
• If a mother has a hemophilia all her sons will
  have the disease and all daughters will be
  carriers
• If a mother is a carrier half her sons will
  inherit the disease and half her daughter will be
  carriers
• Prenatal diagnosis is made by CVS

49
Citations

• www.blc.arizona.edu/Molecular_Graphics/DNA
  structure/DNA_tutorail.HTML
• www.biology.arizonia.edu/cell_bio/tutorials/cell_c
  ycle/cells3.html
• www.biology.arizonia.edu/cell_bio/tutorials/meiosi
  s/page3.html
• M.Golbus,J. Simpson Genetics in Obstetrics and
  Gynecology, 2nd Edition, Philadelphia, W.B
  Saunders Company 1992
• Cunningham,Gant,Leveno,Gilstrap,Hauth,Wenstrom
  Williams Obstetrics, 21st Edition, New York,
  McGraw-Hill Publishing, 2001
• Prenatal Diagnosis of Fetal Chromosomal
  AbnormalitiesObstetrics and Gynecology,Vol
  97,No. 5,May 2001, 2004 Compendium pg605
• Cotran,Kumar,Collins Pathologic Basis of
  Disease, 6th Edition, Philidelphia, W.B Saunders
  Company,1999

50
(No Transcript)
51
(No Transcript)