Genetic Disorders

Genetic Disorders arranged by inheritance mechanism

Autosomal Dominant

1. Structural Protein Deficiencies
1. Achondroplasia (ghr) "fibroblast growth factor receptor 3"
• 80% of cases are due to new mutations in FGFR3 (i.e. sporadic mutation)
• Inheritance of two mutated copies = stillbirth (underdeveloped ribcage -> respiratory failure)
• FGFR3 receptor in bone negatively regulates ossification (i.e. limits formation of bone from cartilage) especially in long bones (i.e. endochondral ossification). FGFR3 mutation --> Gly380Arg (glycine is replaced by arginine in position 380) --> overactive receptor (i.e. gain of function mutation) --> decreased ossification (especially endochondral ossification)--> short limb dwarfism
• membranous ossification is also affected (link) but less apparent
• Images: 1, 2, 3
2. Hereditary Hemorrhagic Telangiectasia (Osler Weber Rendu Syndrome) (ghr) 
• type 1: ENG mutation --> decreased function of "engolin" --> impaired development of boundaries between arteries and veins (usually capillaries that normally bridge the two are lost) --> AVMs (arteriovenous malformation where arteries flow directly into veins. images: 1, 2 ), telangiectases (AVMs near the skin that are visible as red markings; images: 1, 2, 3), hemorrhage (due to high pressure blood in arteries being passed directly into weak walled veins) - especially recurrent epistaxis (nosebleeds, images: 1, 2 )
• type 2 due to ACVRL1 mutation "activin receptor-like kinase 1"
• Juvenile type due to SMAD4 mutation
3. Hereditary Spherocytosis (ghr) "Ankrin-1"
4. Hypercholestrolemia (ghr) "LDL receptors, Apolipoproteins"
5. Marfan's syndrome (ghr) "Fibrillin-1"
6. Osteogenesis Imperfecta (ghr) "type I collagen"
2. Trinucleotide Repeats
1. Huntington's disease (ghr)  "huntington protein"
3. Growth Regulating Protein abnormalities
1. Autosomal Dominant Polycystic Kidney Disease (ADPKD) (ghr) "polycystin-1"
2. Familial Adenomatous polyposis (ghr) APC mutation "adenomatous polyposis coli (tumor suppressor)"
3. Multiple endocrine neoplasias (MEN) (ghr) MEN1 gene - "menin (tumor suppressor)"
4. Neurofibromatosis type 1 (ghr) & 2 (ghr) - NF1 gene "neurofibromin (tumor suppressor)" NF2 gene "merlin aka schwannomin (tumor supressor)"
5. Tuberous sclerosis (ghr) TSC1 gene "hamartin (tumor suppressor)" TSC2 gene "Tuberin (tumor suppressor)"
6. Von Hippel Lindau (vHL) disease (ghr) "VHL protein (tumor suppressor)"

Autosomal Recessive

1. Enzymophathies
1. Albinism 
2. 5 alpha reductase deficiency
3. Familial Adenomatous polyposis (ghr) MUTYH mutation "MYH glycosylase (involved in DNA repair)"
4. Galactosemia
5. MCAD deficiency
6. Phenylketonuria
7. Tay-Sachs disease
8. Wilson's disease (ghr) "copper-transporting ATPase 2"
2. Structural protein deficiencies
1. Autosomal Recessive Polycystic Kidney Disease (ARPKD) (ghr) "fibrocystin (found in cilia)"
2. Cystic Fibrosis  
3. Friedreich ataxia (ghr) trinucleotide repeat (GAA) in FXN gene - "frataxin"
4. Hematochromatosis
5. Kartagener Syndrome
6. Sickel Cell Anemia
7. Thalassemias

X linked Dominant

1. Fragile X syndrome (ghr) "fragile X mental retardation 1 protein (FMRP)" 
2. Hereditary Hypophosphatemic Rickets (ghr) "PHEX enzyme"
• Other forms of inheritance are possible due different gene mutations leading to same disease (phenotype): Dent disease (X-linked recessive), and a rare HHRH with autosomal dominant inheritance
3. Rett Syndrome (ghr) "methyl CpG binding protein 2"

X linked Recessive

1. Enzymopathies
1. Glucose 6 phosphate deficiency (ghr) "glucose 6 phosphate dehydrogenase"
2. X-linked Agammaglobulinemia (ghr) "Bruton tyrosine kinase"
3. Fabry Disease (ghr) "alpha-galactosidase A"
4. Hemophilia A and B (ghr) "coagulation factor VIII and IX, respectively"
5. Lesch-Nyhan Syndrome (ghr) "hypoxanthine guanine phosphoribosyltransferase (HGPRT)" 
6. Ornithine Transcarbamylase deficiency (ghr)"ornithine transcarbamylase"
7. Hunter Syndrome (Mucopolysaccharidosis type II) (ghr) "iduronate 2-sulfatase (I2S)" 
2. Structural Protein Deficiencies
1. Duchenne & Becker Muscular Dystrophy (ghr) "dystrophin" 
2. Kallmann Syndrome (ghr) "fibroblast growth factor receptor 1"
• FGF1 gene mutation --> loss of function mutation --> decreased FGFR1 --> disrupted migration of olfactory neurons and GnRH releasing neurons --> hypogonadism (delayed puberty/ Secondary sex characteristics) & anosmia (loss of smell). 

Karyotype Abnormalities

1. Klinefelter Syndrome (XXY male) [ghr] "most common genetic cause of hypogonadism"
• Tall young man who has trouble conceiving with his wife after a year of trying (infertility). He has long arms and legs, wide hips, bilateral gynecomastia, and small (shrunken) firm testes (no history of trauma, etc).  May also have: sparse facial hair, learning difficulties, decreased libido, Atrial septal defect (ASD)
• Further analysis reveals: fibrosis of seminiferous tubules, and inability to produce sperm (azoospermia), decreased testosterone, increased FSH (indicates primary testicular failure) & LH.
• Karyotype image: 1, 2
• due to meitotic nondisjunction or translocation, the extra X chromosome is turned into a barr body 
• case files: 1,
2. Turner Syndrome (XO female) [ghr]
• 
  
3. Double Y males (XYY male)
4. True Hermaphroditism (46XX or 47XXY)
5. Down Syndrome (trisomy 21)
6. Edwards Syndrome (trisomy 18)
7. Patau Syndrome (trisomy 13)
8. Robertsonian Translocation
9. Cri-du-Chat syndrome (5p-)
10. Williams syndrome (22q11-) [ghr]