Genetic and Developmental Disorders

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Sickle cell disease:

• Missense mutation.

• Adenine replaces thymidine, causing valine to replace glutamic acid in sixth position of beta-globin chain.

• RBCs spontaneously sickle.

Beta-thalassemia major:

• Nonsense mutation.

• Stop codon causes premature termination of DNA transcription.

• Decreased synthesis of hemoglobin A (alpha2beta2).


• Frameshift mutation.

• Defective lysosomal enzyme, hexoaminidase.

Trinucleotide repeat disorders:

• Anticipation.

• Female carriers may be symptomatic.

• Examples: Fragile X, Huntington's disease, Friedreich's ataxia, myotonic dystrophy.

Autosomal dominant diseases:

Hereditary angioedema:

• C1 esterase inhibitor deficiency.

Hereditary spherocytosis:

• Ankyrin.

Familial hypercholesterolemia:

• LDL receptor.


• Neurofibromin.

Autosomal recessive diseases:

Sickle cell anemia:

• Sickle hemoglobin.

G6PD deficiency (Von Gierke):

• G6PD.

Cystic fibrosis:

• CF transmembrane regulator.


• Phenylalanine hydroxylase deficiency.

X-linked recessive diseases:

• Only expressed in males.

• Males transmit mutant gene to all their daughters, who would be asymptomatic.

• Asymptomatic females transmit the gene to 50% of their sons, who would be symptomatic.

• Hemophilia A: factor VIII.

• Eg., Fragile X syndrome, Lesch-Nyhan.

X-linked dominant diseases:

• Expressed in males and females.

• Eg., vitamin D-resistant rickets.

• Alport's disease: hereditary glomerulonephritis with nerve deafness.

Mutations due to Translocations and Deletions

Down syndrome:

• Non-disjunction (most common cause).

• Unequal separation of chromosomes during the first phase of meiosis.

• Robertsonian translocation (second most common cause).

• t(14,21).

Cru du chat syndrome:

• Deletion: Loss of short arm of chromosome 5.

• Mental retardation, cat-like cry, ventricular septal defect.

Edward's syndrome:

• Trisomy 18.

• Mental retardation, VSD, early death.

Patau's syndrome:

• Trisomy 13.

Turner's syndrome:

• Mosaicism. (second most common cause)

• Unequal separation of chromosomes during the first phase of meiosis.

• Non-disjunction: 45, X. (most common cause)

• Short, obese, webbed neck, amenorrhea, normal intelligence, hypothyroidism.

• No barr bodies.

Klinefelter's syndrome:

• Non-disjunction: XXY. (one cause)

• Gynecomastia, soft skin, female hair distribution.

• One barr body.

• Learning disabilities.

XYY syndrome:

• Paternal non-disjunction.

• Aggressive behavior.

• Normal gonadal function.

Prader-Willi and Angelman syndromes:

• Microdeletion of entire gene site on paternal (with corresponding maternal inactivation) and maternal (with corresponding paternal inactivation) chromosomes 15, respectively.

Sexual development:

No Y chromosome:

• Germinal tissue differentiate into ovaries.

Y chromosome present:

• Germinal tissue differentiate into testes.

• MIF, testosterone, 5alpha-reductase, DHT present.

Testicular feminization:

• XR.

• Deficiency of androgen receptors.

• Vagina ends in a blind pouch.

• Normal male levels of testosterone and DHT - but no receptors.

• Genotypically male, but phenotypically female.

Congenital malformations:

• Occur between third and ninth weeks of pregnancy.

• SLE = heart block in new-born.

• Diabetes mellitus = neural tube defects + heart disease in new-born.

• Hypothyroidism = cretinism in new-born.

• HOX gene mutation (getting acne treatment during pregnancy) = abnormal craniofacial development.


• Decreased amniotic fluid.


• Amniocentesis: genetic defects.

• Ultrasound: rule out neural tube defects.

• AFP: increased in neural tube defects.

• Down syndrome: decreased AFP and urine estriol; increased hCG.

Additional Reading:

Basic Pathology

1. Cell Injury
2. Inflammation and Repair
3. Immunopathology
4. Water, Electrolyte, Acid-Base, Hemodynamic Disorders
5. Genetic and Developmental Disorders
6. Environmental Pathology
7. Nutritional Disorders
8. Neoplasia
9. Vascular Disorders
10. Heart Disorders
11. Red Blood Cell Disorders
12. White Blood Cell Disorders
13. Lymphoid Tissue Disorders
14. Hemostasis Disorders
15. Blood Banking and Transfusion Disorders
16. Upper and Lower Respiratory Disorders
17. Gastrointestinal Disorders
18. Hepatobiliary and Pancreatic Disorders
19. Kidney Disorders
20. Lower Urinary Tract and Male Reproductive Disorders
21. Female Reproductive and Breast Disorders
22. Endocrine Disorders
23. Musculoskeletal Disorders
24. Skin Disorders
25. Nervous System Disorders
26. Notes on Tissue Regeneration
27. A Table of Bleeding Disorders
28. FAQ on Structure and Function of Red Blood Cells
29. FAQ on Components of Blood
30. Notes on Hemostatic Mechanisms
31. What is Fever?
32. What is Edema?
33. FAQ on Blood Pressure
34. FAQ on principles of fluid and flow dynamics of Blood
35. Causes of Thrombocytopenia
36. Squamous cell carcinoma of head and neck mucosa
37. Four tumors which never metastasize to the brain
38. What is caustic injury?
39. What causes Peripheral Edema?

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