This document discusses genetic diseases and abnormal fetal development. It begins with definitions of genetic terms like genetic code, chromosomes, genes, and cell division. It then discusses abnormal fetal development including malformations, deformations, and disruptions caused by chromosomal abnormalities, genetic defects, and environmental factors. The document ends by covering perinatal pathology including birth defects and metabolic disorders.

1. Genetic Diseases

2. Outline
I. Definitions
Genetic code
Chromosomes, Genes, Cell Division
Molecular mechanisms
II. Abnormal fetal development
Malformations, deformations, dysplasias,
disruptions
III. Perinatal pathology
Birth defects
Metabolic disorders

3. The Cell

4. Nucleus
• DNA: arranged in chromosomes
(network of granules = nuclear chromatin)
• RNA: spherical intranuclear structure(s)
- nucleolus / nucleoli

5. Genetic Code
 A series of messages contained in the
chromosomes
This code regulates cell functions by way of
directing the synthesis of cell proteins
 The code corresponds to the structure of the
DNA
 The code is transmitted to new cells during
cell division

6. DNA structure

7. DNA replication

8. mRNA and tRNA

9. Chromosomes
• Exist in pairs – homologous: 22a + 1s
• Composed of double coils of DNA
• Basic unit: nucleotide
phosphate group
deoxyribose sugar
base: purine (A, G)
pyrimidine(T,C)

10. Genes
• A locatable region of genomic sequence,
corresponding to a unit of inheritance
• A union of genomic sequences encoding a
coherent set of potentially overlapping
functional products; i.e. genes are one long
continuum (2007)
• Determine cell properties, both structure and
functions unique to the cell

11. Genome
 Sum total of all genes contained in a cell’s
chromosomes
 Identical in all cells
 Not all genes are expressed in all cells
 Not all genes are active all the time
 May code for enzymes or other functional
proteins, structural proteins, regulators of
other genes

12. Gene Product
A protein or RNA specified by a gene
 Transcribed into mRNA in the nucleus
 Translated through tRNA and cytoplasmic
ribosomes into protein

13. Human Genome
 3 billion+ pairs of DNA nucleotides
 ~ 50,000 – 100,000 genes
 Protein-coding Genes = <10% (2%) of human genome
 Exons: parts of the DNA chain that code for specific proteins
 Introns: the parts in-between the exons
 Both exons and introns are transcribed but only the exons
are translated (introns are removed from mRNA before
leaving nucleus)

14. Sex chromosomes
☺ Genetic sex = composition of X and Y
☺ Large X: many genes, many activities
☺ Small Y: almost entirely male sexual diff.
☺ Female: XX, male XY
☺ One X randomly inactivated and
nonfunctional after first week of embryonic
development
☺ Same inactivated X in descendant cells

15. (Mary) Lyon Law

16. Barr body

17. Y chromosome
 Stains with some fluorescent dyes
 -bright fluorescent spot in the nucleus
 Normal female: sex chromatin body
but no fluorescent spot
 Normal male: fluorescent spot
but no sex chromatin body

18. Cell Division
• Mitosis: somatic cells (PMAT)
Daughter cells have the same number of
chromosomes as the parent cell.
• Meiosis: gametogenesis (1st and 2nd div)
Number of chromosomes reduced by half.

19. Chromatids
• Before mitosis, the DNA chains duplicate to
form new chromosome material.
The duplicated chromosome material lies side
by side = two sister chromatids.
Mitosis = the process by which conjoined
chromatids separate into sister chromatids
and move into new daughter cells.

20. Mitosis
• Interphase: DNA duplication to form chromatids
just before mitosis
• Prophase: centriole migration, mitotic spindle
• Metaphase: chromosomes line up in centre,
chromatids still joined at centromere
• Anaphase: chromosomes separate into sister
chromatids
• Telophase: sister chromatids form new
chromosomes, new nuclear membranes form,
cytoplasm divides

21. Mitosis

22. Meiosis
• First meiotic division interphase: duplication of
chromosomes to form paired chromatids
• Prophase 1 of meiosis: homologous chromosomes
lie side by side over entire length = synapse.
Interchange of segments of homologous
chromosomes = crossover.
2 Xs side by side just like the autosomes.
X and Y end-to-end: no crossover.

23. Meiosis
• Metaphase 1: paired homologous chromosomes
align at the equatorial plate
• Anaphase 1: homologous chromosome pairs
migrate to opposite poles of the cell;
each chromosome is composed of two chromatids,
the chromatids are not separated
• Telophase 1: two new daughter cells form;
each contains half the chromosome number =
reduction of chromosomes by half; interchange of
genetic material occurred during synapse

24. Meiosis
• Second meiotic division = mitotic division
Prophase 2: DNA does not replicate
Metaphase 2: chromosomes align at the
equatorial plate
Anaphase 2: sister chromatids migrate
separately
Telophase 2: four haploid cells (half the normal
number of chromosomes)

25. Meiosis

26. Gametogenesis
 Gonads: testes, ovaries; contain
 Precursor cells or germ cells; mature into
 Gametes: sperm, ova; in gametogenesis
 Spermatogenesis, oogenesis

27. Gametogenesis

28. Primary follicles

29. Oogenesis vs. spermatogenesis
 One ovum (+ 3 polar bodies) vs. four spermatozoa
 Oocytes formed before birth vs. continuous
spermatogenesis (‘fresh’ sperm)
Prolonged Prophase 1 until ovulation –
more frequent congenital abnormalities in ova of
older women (longer exposure to potentially harmful
environmental influences until meiotic division
resumes at ovulation)

30. Chromosome Analysis

31. Karyotype

32. Genes and Inheritance
• Locus: specific site of a gene on the chromosome.
Since the chromosomes exist in pairs, genes are also
paired.
• Alleles: alternate forms of a gene can occupy the
same locus (homozygous, heterozygous)
• Recessive gene: expressed only when homozygous
• Dominant gene: expressed whether homozygous or
heterozygous, both expressed when co-
dominant
• Sex-linked gene: only X-linked in males, most are
recessive, hemizygous (no allele on Y)

33. Gene Imprinting
• Genes occur in pairs on homologous
chromosomes, one from each parent
• Different effects of gene whether ♀ or ♂
Genes modified during gametogenesis
• Gene imprinting: additional methyl groups
added to DNA molecules
• Basic structure unchanged;
in some diseases different expression
(behaviour) depending on parent of origin:
hereditary disease as a result of imprinting

34. Genetic Engineering
• Insertion of a gene encoding a desired
product (e.g. insulin) into a bacterium
• Bacterial gene spliced enzymatically,
recombinant DNA inserted into plasmid
(circular DNA segment in bacterium), dividing
bacterial population produces desired protein

35. Gene Therapy
• Normal gene inserted into defective cell
• Compensates for the missing or
dysfunctional gene, in somatic cells only
• Can be inserted into mature cell (ly)
• Can be inserted into stem cell (bone marrow)
• Used to treat e.g. ADA deficiency, CF, …

36. Congenital / Hereditary Diseases
• Congenital: present at birth
• Hereditary (genetic): result of chromosome
abnormality or defective gene

37. Causes of malformations
1. Chromosomal abnormalities
2. Gene abnormalities
3. Intrauterine injury (e.g. drugs, radiation,
infection, environmental, etc)
4. Environmental effect on genetically
predisposed embryo

38. Chromosomal abnormalities
• Nondisjunction: failure of homologous
chromosomes in germ cells to separate from
one another during 1st or 2nd meiotic division
• Sex chromosomes or autosomes
• Extra chromosome: trisomy (24 or 47)
Absent chromosome: monosomy (22 or 45)

39. Nondisjunction in meiosis

40. • Chromosome Deletion: Broken piece of
chromosome is lost from cell
• Translocation: Not lost, just misplaced and
attached to another chromosome
- reciprocal: between two nonhomologous
chromosomes (no loss or gain of genetic
material - no loss of cell function)
- in germ cells: deficient or excess
chromosome material – abnormal zygote

41. Translocation in gametes

42. Sex chromosome abnormalities

43. Turner syndrome

44. Klinefelter syndrome

45. Autosomal abnormalities
☺ Loss of genetic material: aborted embryo
☺ Deletion of gene: congenital anomalies
☺ Trisomy: syndromic, e.g. 21, 18, 13

46. Trisomy 21 (Down)

47. T21 causes
1. Nondisjunction during gametogenesis (95%)
2. Translocation (few)
3. Nondisjunction in zygote (rare)

48. Translocation T21

49. Zygote nondisjunction T21- Mosaic

50. Abnormal gene diseases
☺ Individual gene abnormalities
☺ Hereditary diseases transmitted mostly on
autosomes, only a few on sex chromosomes.
☺ Gene mutation: spontaneous
environmental
☺ Minor structural change may result in major
functional abnormality (e.g. SCD: HgbSA, co-
dominant, Hgb beta gene)

51. Modes of Inheritance
☺ Autosomal dominant (a dominant gene expressed
in the heterozygous state)
☺ Autosomal recessive (expressed only in
homozygous individual, disease only if both alleles
are abnormal, carrier if only one abN)
☺ Codominant (full expression of both alleles in
heterozygous state)
☺ X-linked (usually affects male offspring; the
abnormal X-linked gene acts as dominant gene when
paired with the Y chromosome)

53. Intrauterine Injury
1. Drugs: thalidomide (phocomelia), DES
(cervical cancer), street drugs (IUFD),
smoking (IUGR), alcohol (FAS), etc
2. Radiation: x-rays
3. Maternal infections:
- Rubella virus (CVS, CNS, chr. infection)
- CMV (microcephaly, chronic infection)
- Toxoplasma gondii (hydrocephalus,
systemic infection)

54. Thalidomide baby

55. Prenatal CMV infection

56. Multifactorial Inheritance
☺ Combined effect of multiple genes
interacting with environmental agents,
e.g. cleft palate, cardiac malformations, club
foot, hip dislocation, spina bifida, etc
☺ Cause: developmental sequence fails to
reach a certain point at an appropriate time
(threshold)

57. Genetically determined variation
in rate of development

58. Effect of harmful environmental agents on
susceptibility for
congenital malformations

59. Interaction of genetic predisposition
and environmental factors
in cleft palate

60. Prenatal Diagnosis
of Congenital Abnormalities
1. Examination of fetal cells for chromosomal,
genetic or biochemical abnormalities
2. Examination of amniotic fluid for products
secreted by the fetus
3. Ultrasound of the fetus to detect
malformations (NTD, hydrocephalus, PCKD,
etc)

61. Prenatal Diagnosis
of Congenital Abnormalities

62. Main indications for amniocentesis
1. Maternal age (>35)
2. Previous infant with T21 or other
chromosomal abnormality
3. Known translocation T21 carrier
4. Other chromosomal abnormality in either
parent, e.g. t(7;21)
5. Risk of genetic disease in the fetus that can
be detected prenatally (thalassemia)
6. Previous infant born with neural tube defect
(multifactorial inheritance, ~5%)

63. Methods of fetal DNA analysis
1. Enzyme analysis of DNA: resultant
DNA fragments different in health and
disease, e.g. sickle cell anemia
2. DNA probes: same complementary
nucleotide arrangement as in defective DNA
gene – binds to mutant gene

64. Molecular Genetics of
Solid Pediatric Tumors
Mechanisms for tumor development
1. Creation of novel fusion proteins
2. Loss of tumor suppressor genes
3. Activation of proto-oncogenes

65. NB: MYCN amplification and
1p deletion by FISH

66. RB: MYCN probe to detect
homogeneously staining region in metaphase
spread and interphase nuclei

67. Ewing sarcoma: t(11;22)
EWS green, FLI-1 pink, t yellow

68. E-RMS: Spectral karyotype
t(1;3), t(1;15), t(1;21)

69. Abnormal Fetal Development
• Malformation
• Deformation
• Dysplasia
• Disruption

70. Prenatal development, pre-embryonic

71. Prenatal development, early embryonic

72. Prenatal development, late embryonic

73. Fetal development

74. Normal gametogenesis

75. Meiosis

76. Abnormal gametogenesis

77. ♂ & ♀ gametes

78. Sperm penetrating oocyte

79. Fertilization

80. Causes of human congenital anomalies

81. Malformations
• Intrinsic abnormalities of blastogenesis and
organogenesis affecting the
morphogenetically reactive fields of the
embryo = developmental field defects
• Occur alone or in combination (syndromes or
associations)
• Severe (spina bifida aperta) or
mild (spina bifida occulta)

82. Malformations
• Causally heterogeneous
• Intrinsic causes: mendelian mutations,
chromosome abnormalities,
environmental interactions (multifactorial),
mitochondrial mutations

83. Disruptions
• Environmental (exogenous) causes producing
abnormalities of morphogenetic field
dynamics
• E.g. rubella, thalidomide, isotretinoin,
alcohol, etc

84. Rubella embryopathy

85. Diabetic embryopathy

86. Dysplasias
• Disturbances of histogenesis, occurring later
and somewhat independently of
morphogenesis
• Morphogenesis is prenatal,
histogenesis continues postnatally in all
tissues that have not undergone
end differentiation
• Dysplasias may predispose to cancer

87. Neurofibromatosis

88. Tuberous sclerosis

89. Deformities
• Secondary changes in form or shape of
previously normally formed organs or body
parts
• Caused by extrinsic forces (e.g. Potter
syndrome) or intrinsic defects (e.g.
fetal akinesia syndrome with congenital
arthrogryposis)

90. Oligohydramnios (Potter) sequence

91. Arthrogryposis

92. Sequences
• Secondary consequences of malformations,
disruptions, dysplasias, or deformities
• E.g. renal adysplasia leads to Potter
oligohydramnios sequence
DiGeorge anomaly leads to tetany,
hypoparathyroidism, heart failure,
conotruncal congenital heart defect

93. Minor Anomalies
• Disturbance of phenogenesis in fetal life
• Phenogenesis: the process of attaining final
quantitative anthropometric traits of the race
and family (variant familial developmental
pattern)
• Causes:
intrinsic (chromosome imbalance)
extrinsic (teratogens)

94. Syndromes
• Patterns of anomalies proven or presumed
causally related
• Causes:
- chromosome mutations
- imprinting defects
- aneuploidy
- multifactorial disorders
- teratogenic sequences

95. Treacher-Collins syndrome
(mandibulofacial dysostosis) AD

96. Leprechaunism
(defective insulin binding) AR

97. Associations
☺ Idiopathic multiple congenital anomalies of
blastogenesis
Vertebral anomalies V
Anorectal anomalies A
TracheoEsophageal defects TE
Radial and Renal defects R
☺ Single hit during gastrulation affecting multiple,
morphogenetically closely related structural
primordia

98. Metabolic Disorders
☺ Most are inherited as AR, some are
X-linked, a few are AD.
☺ Great variability in presentation
☺ Some present with dysmorphic features
☺ Storage material in RES and other tissues

99. Storage Diseases
☺ Lysosomal Lipid Storage Diseases
Nieman-Pick: sphyngomyelin
Gaucher disease: glucocerebrosidase
Tay-Sachs disease: Gangliosidoses
Metachromatic leukodystrophy
☺ Mucopolysaccharidoses (I, II, III, VII)
glycosaminoglycans and glycolipids

100. Hurler syndrome (MPS 1A) AR

101. COH Disorders
☺ Glycogen Storage Diseases
☺ Galactosemia

102. Glycogen storage disease type II

103. Amino Acid Disorders

104. Misc.
• Fatty Acid Beta-Oxidation Defects (LCAD,
MCAD, SCAD)
• Organic Acidemias
• Defects in Purine Metabolism
• Carnitine Deficiency
• Peroxisomal Disorders
• Disorders in Metal Metabolism
• Defects in Copper Metabolism

105. Thank you