I.
Autosomal Recessive Disorders
General Rule: Often involves "Loss of Function" in enzymes. Onset is usually early in childhood.
Disease Gene/Locus Detailed Pathogenesis Clinical & Diagnostic Keys
$\beta$- HBB (11p15) Point mutations in promoter or splicing sites Target cells, "Crew-cut"
Disease Gene/Locus Detailed Pathogenesis Clinical & Diagnostic Keys
thalassaemia → low $\beta$-globin → unpaired $\alpha$- appearance on skull X-ray,
chains precipitate, damaging RBC membrane. Chipmunk facies.
Howell-Jolly bodies,
Glutamic acid $\rightarrow$ Valine at
Sickle Cell Anemia HBB (11p15) autosplenectomy (by age
position 6. Deoxygenated HbS polymerizes.
5), dactylitis.
Phe508 deletion → misfolded protein Meconium ileus in
Cystic Fibrosis CFTR (7q31) degraded in ER → no $Cl^-$ secretion newborns, Pseudomonas
$\rightarrow$ thick mucus. infections, Nasal polyps.
Kayser-Fleischer rings,
Defect in copper-transporting ATPase →
ATP7B low serum ceruloplasmin,
Wilson’s Disease failure to incorporate copper into
(13q14) basal ganglia
ceruloplasmin.
degeneration.
Prussian blue stain
Mutation (C282Y) → low Hepcidin levels →
Hemochromatosis HFE (6p22) positive in liver, "Bronze
uncontrolled iron absorption.
Diabetes," Arthropathy.
Severe sunburn,
Xeroderma Defective Nucleotide Excision Repair (NER);
XP genes telangiectasia, 1000x
Pigmentosum cannot repair pyrimidine dimers.
increased skin cancer risk.
Ochronosis (blue-black
Homogentisate 1,2-dioxygenase deficiency
Alkaptonuria HGD (3q) cartilage), urine turns
$\rightarrow$ high Homogentisic acid.
black on exposure to air.
Phenylalanine hydroxylase deficiency Musty/Mousy odor,
PKU PAH (12q) $\rightarrow$ Phenylalanine converted to intellectual disability,
phenylketones. microcephaly.
II. Autosomal Dominant Disorders
General Rule: Often involve structural proteins or receptors. Shows "Vertical Inheritance" (every generation
affected).
Disease Gene/Locus Detailed Pathogenesis Clinical & Diagnostic Keys
Familial Two-hit hypothesis; mutation in a tumor 100% progress to colon
APC (5q21)
Adenomatous suppressor gene regulating Wnt signaling. cancer; requires
Disease Gene/Locus Detailed Pathogenesis Clinical & Diagnostic Keys
Polyposis prophylactic colectomy.
Polycystin defect affects primary cilia Bilateral large kidneys,
Adult Polycystic PKD1 (16p) /
sensing $\rightarrow$ overproliferation of Berry aneurysms (Circle
Kidney (ADPKD) PKD2 (4q)
tubular cells. of Willis), Liver cysts.
Mutation in Neurofibromin (a GAP) Lisch nodules (iris), Cafe-
Neurofibromatosis 1 NF1 (17q11) $\rightarrow$ persistent RAS activation au-lait spots, optic
$\rightarrow$ cell growth. gliomas.
Subluxation of lens
Fibrillin-1 defect $\rightarrow$ TGF-
(upward), Aortic
Marfan Syndrome FBN1 (15q21) $\beta$ signaling dysregulation
dissection, Pectus
$\rightarrow$ weak elastic fibers.
excavatum.
Increased MCHC, positive
Hereditary Defect in Ankyrin/Spectrin → loss of
ANK1 (8p) Osmotic Fragility test,
Spherocytosis membrane → RBCs become spheres.
Splenomegaly.
Gain-of-function mutation → inhibits
Short limbs, frontal
Achondroplasia FGFR3 (4p16) chondrocyte proliferation at growth
bossing, trident hand.
plates.
Blue sclera, multiple
fractures, dental
Osteogenesis Qualitative or quantitative defect in Type 1
COL1A1/2 opalescence
Imperfecta Collagen (triple helix).
(Dentinogenesis
imperfecta).
III. Sex-Linked (X-Linked) Disorders
General Rule: Recessive forms affect males (XY). Dominant forms affect both but are often lethal in males.
Disease Type Mechanism Clinical & Diagnostic Keys
Gowers' sign,
Duchenne Muscular X-L Frameshift mutation $\rightarrow$ total
pseudohypertrophy of calves,
Dystrophy Rec. absence of Dystrophin (anchors muscle).
elevated Creatine Kinase.
X-L Factor VIII deficiency Increased PTT, normal
Hemophilia A
Rec. $\rightarrow$ failure of intrinsic PT/Bleeding time. Hemarthrosis.
pathway.
Low NADPH $\rightarrow$ low Reduced
X-L Heinz bodies and Bite cells on
G6PD Deficiency Glutathione $\rightarrow$ RBCs cannot
Rec. peripheral smear.
buffer $H_2O_2$.
Absent B-cells and Tonsils;
Bruton’s X-L Defect in BTK (tyrosine kinase)
recurrent bacterial infections
Agammaglobulinemia Rec. $\rightarrow$ B-cells don't mature.
after age 6mo.
NADPH Oxidase defect Negative Nitroblue Tetrazolium
Chronic Granulomatous X-L
$\rightarrow$ lack of superoxide (NBT) test; catalase (+)
Disease Rec.
radicals. infections.
X-L CGG trinucleotide repeat expansion in Large ears, long face,
Fragile X Syndrome
Rec. FMR1 gene. macroorchidism (large testes).
IV. Special Categories (Codominant & Mitochondrial)
Disease Inheritance Mechanism Clinical Key
$\alpha$ 1- Misfolded protein (PiZ allele)
PAS-positive globules in liver;
antitrypsin Codominant accumulates in ER of
Panacinar emphysema in lungs.
deficiency hepatocytes.
Permanent bilateral loss of central
Leber Hereditary Mutations in NADH
Mitochondrial vision; strictly maternal
Optic Neuropathy dehydrogenase (ETC Complex I).
inheritance.