BPM: FTM Patterns of Inheritance Disorders
AUTOSOMAL DOMINANT
Overall Characteristics:
 Manifest in heterozygotes usually
 Vertical inheritance
 Male: female = same
 Homozygous symptoms worse/lethal –RARE
 Recurrence rule: affected/heterozygotes= 1/2
DISEASE
`yMolecular Mechanism:
 Haploinsufficiency: ↓% of normal gene products, ∴


not enough for normal function
Dominant-negative: mutant gene product interferes
function of normal gene product
Gain of Function: ↑expression of new gene product
CHARACTERISTICS
Familial Hypercholesterolemia
(LDL receptor Deficiency)
Huntington Disease
MOLECULAR MECHANISM
+MANIFESTATION
-Haploinsufficiency
-Triplet repeat  CAG
-Delayed onset
-Gain of Function
-Incomplete penetrance
-Anticipation
-Triplet repeat  CTG (3’UTR)
-DMPK gene
Myotonic Dystrophy
-S: muscle wasting, cataracts, heart
conduction defects, endocrine changes,
myotonia
-Fibrillin-1 gene
Marfan Syndrome
Osteogenesis Imperfecta
Achondroplasia
-s: skeletal abnormalities, hypermobile
joints, ocular abnormalities,
cardiovascular issues
-COL1A1 + COL1A2 (collagen) gene
-S: brittle bones, blue sclera
-FGFR3: cartilage  bone
-S: severe stunting in growth  lethal in
-Pleiotropy (affects multiple organs)
-Anticipation
-Dominant Negative
-Pleiotropy
-Hot spots
-Locus Heterogeneity, hot spots
-Pleiotropy, variable expression
-Type 1: HI Type II, III, IV: DN
-Gain of Function
-Hot spots  new mutations
homozygotes
Neurofibromatosis Type 1
-NF-1(tumor suppressor) 
inactivates RAS-GTP
-S: Neurofibromas, lisch nodules in iris,
café-au-lait spots
Acute Intermittent Porphyria
-High penetrance
-Variable expression
-Hot spots  new mutations
-Allelic heterogeneity
-Haploinsufficiency
AUTOSOMAL RECESSIVE
Overall Characteristics:
 Expressed in homozygotes
 Carriers/Heterozygotes = phenotypically
normal
 Both parents = carriers
 Horizontal Inheritance (skip generations)
 Male: female = same
 Consanguinity increase incidence
 Recurrence rule:
o Homozygous: 1/4
o Heterozygotes/carriers: 2/3 rule
o Offspring of affected: 1/2
DISEASE
Cystic Fibrosis
Sickle Cell Anemia
Phenylketonuria (PKU)
Tay-Sachs Disease
Congenital Deafness
Hemochromatosis
Alkaptonuria
Homocystinuria
Galactosemia
⍺1-Tripysin Deficiency
SCID
Molecular Mechanism:
 Loss of function: reduced activity or complete loss of
gene product, protein produced from normal allele
(50%) enough to carry out normal function

Pseudo-autosomal dominance: Aa x aa (carrier x
affected)  looks like AD
Factors ↑ AR incidence:
o Consanguinity
o Heterozygote advantage
o Genetic isolation
o Assortative mating (“like x “like”)

CHARACTERISTICS
-CFTR  frame shift
-S: respiratory failure
-β-globin gene
MOLECULAR MECHANISM
+MANIFESTATION
-Allelic heterogeneity 
compound heterozygotes (Diff
mutation from each parent)
-Pseudo-autosomal dominant
-Hexoaminidase deficiency
-Locus heterogeneity
-HFE gene  most common C282Y
mutation (cys  tyr)
-Delayed onset
-Delayed onset
-ADA deficiency  build-up of dATP
-Allelic heterogeneity
-Locus Heterogeneity (because of
X-linked type)
Xeroderma Pigmentosum
X-LINKED DOMINANT
Molecular Mechanism:
 Asymmetric/Skewed X-inactivation: ∴
variable expressivity in females
Overall Characteristics:
 Vertical inheritance
 Females > males
 NO male to male transmission
 Affected male  ALL daughters =
AFFECTED, ALL sons = NORMAL
DISEASE
Rett Syndrome
Incontinentia Pigmenti
Vitamin D Rickets
CHARACTERISTICS
-Male: lethal
-Male: lethal
-S: rashes, blisters, patches of
hyperpigmentation, intellectual learning
disability, retinal detachment
MOLECULAR MECHANISM
+MANIFESTATION
-Asymmetric X-inactivation
X-LINKED RECESSIVE
Overall Characteristics:
 Incidence: male > female (male only need 1
copy to express disease)
 Horizontal inheritance
 Affected male  daughters = OBLIGATE
CARRIERS
 NO male to male transmission
DISEASE
Duchenne/Becker Muscular
Dystrophy
Molecular Mechanism:
 Asymmetric/Skewed X-inactivation: in
females. . . active mutant cells > normal cells
 manifesting heterozygote
CHARACTERISTICS
-Dystrophin gene
-Duchenne = severe  males don’t
survive
-Becker = mild
G6PD Deficiency
-S: hemolytic anemia
Hemophilia A + B
-Clotting Factor VIII deficient
-S: hemarthrosis, subcutaneous hematoma
MOLECULAR MECHANISM
+MANIFESTATION
-Hot spots
-Asymmetric X-inactivation
-Allelic Heterogeneity
Lesch-Nyhan Syndrome
Red-green color blindness
SCID
Fragile-X
-SCIDX1  defect in y-chain of
interleukin IL2RG = T-cell lacks receptor
∴ can’t mature ∴↓ normal B-cells
-Triplet Repeat  CGG (promoter
region)
-Locus Heterogeneity (because of
AR type)
Terminologies/Definitions
 Locus heterogeneity: mutation on different genes
 Allelic heterogeneity: mutation on same gene
 Compound heterozygote: having 2 different types of mutation  locus or allelic heterogenetic disease
 Digenic Disorders: mutations in 2 genes that are additive to produce disorder phenotype
 New Mutation: no family history of disease  mutation transmitted from unaffected parent to affected
offspring
o Common in diseases that have hot spots
o Sometimes due to increased age of parent
 Germline Mosaicism: father unaffected but some offspring affected  due to mutation in germline
cells
 Heteroplasmy: variable expressivity in mitochondrial disorders  due to passive segregation of
mitochondrial DNA (“dose” of mutated mitochondria DNA varies)
 Anticipation: Due to unstable triplet repeats, repeats expand each generation; ↑instability  severity
increases