Lecture 12: Genetic Diseases Flashcards
Types of genetic diseases
- Cytogenetic disorders
- Single gene disorders
- Multifactorial genetic diseases
Cytogenetic disorders
Result from alterations in number or structure of chromosomes (autosomal or sex)
Causes of numeric chromosome changes
- Nondisjunction of homologous chromosome pairs at meiosis I
- Failure of sister chromatids to separate in meiosis II
- Mosaicism
Structural changes in chromosomes
- Translocation
- Deletion
- Inversion
- Ring chromosome
Isochromosomes
Translocation at centromere; essentially swaps chromosome arms
Autosomal chromosome disorders
Result from loss or gain of all/part of autosomal chromosome.
General trisomy phenotype
- Low birth weight
- Short stature
- Failure to thrive
- Severe intellectual disability
- Multiple organ systems affected
Down Syndrome
Trisomy 21
- Upslanting palpebal fissures, low-set small folded ears, short neck, flattened nasal bridge, Brushfield spots, epicanthal folds
- Early onset Alzheimer’s
- Increased AML/ALL risk
Edwards Syndrome
Trisomy 18
- Only 5-10% survival past 1 year
- Microcephaly, cleft lip, heart defects
Patau Syndrome
Free trisomy 13, or trisomy 13 w/ Robertsonian translocation
- Median survival ~5 days if live born
- Cardiac defects, polydactyly, capillary hemangiomas
Common features of all trisomies
Eyes, ears, neck, heart, feet, hands, intellect
Sex chromosome cytogenetic disorders
Gain or loss of all/part of sex chromosome; often produces subtle changes. Commonly manifests infertility.
Klinefelter Syndrome
XXY. Male hypogonadism
Turner Syndrome
X. Primary hypogonadism, phenotypic female
Single gene disorders
Submicroscopic changes to 1 gene.
- Mendelian (autosomal dominant/recessive, X-linked)
- Non-traditional (mitochondrial, triple repeat)
Types of genes affected by single gene disorders
Structural proteins:
- Marfan syndrome
- Ehlers-Danlos syndrome
Receptor proteins/channels:
- Familial hypercholesterolemia
- Cystic fibrosis
Enzymes:
- Lysosomal storage diseases
- Glycogen storage diseases
Mutations in protein-coding genes
- Point
- Frameshift
- Trinucleotide repeat
Steps to evaluating a pedigree
- Transmission (horizontal/vertical)
- Sex differences (male to female ratio)
- Segregation (male to male, % children affected, etc.)
Marfan Syndrome
FBN1 fibrillin gene mutation; CT disorder
- Tall stature, long fingers, bilateral lens dislocation, mitral valve prolapse, aortic aneurysm
Ehlers-Danlos Syndrome
13 variants each w/ distinct mutation
- Defects in collagen synthesis/assembly
- Classic = collagen V synthesis deficiency
- Fragile hyperextensible skin, hypermobile joints, poor wound healing
Familial hypercholesterolemia
Mutant LDLR gene (incomplete autosomal dominant)
- Heterozygotes have early middle age heart disease
- Homozygotes have fatal heart disease in early childhood
- 5 classes of LDLR mutations
- Obesity, chest pain, high cholesterol, xanthomas
Lysosomal storage diseases
E.g. Tay-Sachs
- Hexosaminidase A deficit -> GM2 ganglioside accumul. -> progressive neural destruction
- Cherry red eye spot, neuron lipid accumulation
- Optimal for carrier screening; higher among Ashkenazi Jews, French-Canadians (Hex A activity)
Cystic fibrosis
Mutant CFTR gene (chloride channel)
- Meconium ileus, respiratory infections, greasy foul stools, malnutrition, male infertility
- Sweat test
- Over 1000 known mutations, delF508 most common
- Different mutations -> varied phenotype
Hypophosphatemic rickets
(Vit. D resistant rickets)
Renal phosphate transport disorder; X-linked dominant
- Mutant PHEX gene on Chr Xp
- Poor Vit. D metabolism -> skeletal/dental problems
