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Genetic and Developmental Disorders

Sickle cell disease:

Missense mutation.

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

RBCs spontaneously sickle.

Beta-thalassemia major:

Nonsense mutation.

Stop codon causes premature termination of DNA transcription.

Decreased synthesis of hemoglobin A (alpha2beta2).

Tay-Sachs:

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.

Neurofibromatosis:

Neurofibromin.

Autosomal recessive diseases:

Sickle cell anemia:

Sickle hemoglobin.

G6PD deficiency (Von Gierke):

G6PD.

Cystic fibrosis:

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CF transmembrane regulator.

PKU:

Phenylalanine hydroxylase deficiency.

X-linked recessive diseases:

Only expressed in males.

Males transmit mutant gene toall their daughters, who would be asymptomatic.

Asymptomatic females transmit the gene to50% 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:

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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.

Oligohydramnios:

Decreased amniotic fluid.

Tests:

Amniocentesis: genetic defects.

Ultrasound: rule out neural tube defects.

AFP: increased in neural tube defects.

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