MAJOR MODES OF INHERITANCE

Steps to follow in every mode of inheritance:

-First recognize the mode of inheritance
-Predict the recurrence risk
-Identify carriers (obligate)
MODE OF INHERITANCE CHARACTHERISTICS EXAMPLES
AUTOSOMAL DOMINANT -Vertical appearance -Familial
NOTE: requires only one copy of -Disease in every hypercholestherolemia (LDL
the mutation to produce the generation receptor deficiency)
disease. -Observed in multiple -Huntington disease
-Affected individuals must generations of a pedigree -NF type 1
receive a disease-causing gene -Skipped generations are -Marfan Syndrome
from an affected parents So not typically seen; cuz 2 -Acute intermittent
identified first which one is the unaffected parents cant porphyria
affected parent (PROBAND) to transmit a disease-causing
assign the capital A allele to their offspring.
RECURRENT RISK:
A: mutant gene. -Both parents homozygous:
a: normal allele. 50%.
-Both parents
heterozygous: 75%
AUTOSOMAL RECESSIVE -Horizontal appearance -Sickle cell anemia
NOTE: are clinically expressed -Disease skip generations; -Cystic Fibrosis
only in the homozygous commonly seen only in one -Phenylketonuria (PKU)
(produced by the union of 2 generation of the pedigree. -Tay-Sachs disease
heterozygous parents) state; RECURRENT RISK: (Hexosaminidase A
the offspring must inherit one -Homozygous normal for deficiency)
copy of the disease-causing the two alleles: 25% NOTE: most genetic-based
allele from EACH parent. -Homozygous for the diseases are inherited this
mutant gene: 25% way.
A: normal allele. -Heterozygous carrier:
a: mutant gene. 50%
 MODE OF INHERITANCE
X-LINKED RECESSIVE
No male to male
transmission cuz the father
give the Y chromosome to
the sons; and the disease is
X-linked and the X
chromosome is given for the
mother.
X: normal allele.
x:mutant gene.
X_LINKED DOMINANT
X: mutant gene.
x: normal allele.
CHARACTHERISTICS
-Gene located on X
chromosome
-Horizontal appearance
-Disease skips generations
-Mostly affects MALES
-NO male to male
transmission.
RECURRENT RISK:
-If the fetal sex is known; the
RR for daughters is 0%, for
sons is 50%.
-If the fetal sex is unknown
the RR is 25% for each sex.
-Gene located on X
chromosome
-Vertical appearance
-Disease in EVERY generation
-NO male to male
transmission
-Affected males transmit to
ALL daughters.
RECURRENT RISK:
-If the fetal sex is known:
daughters 100%, sons 0%
-If the fetal sex is unknown
50% for each sex.
EXAMPLES
-Duchenne muscular
dystrophy
-Lesch-Nyhan sdx (HGPRT
deficiency)
-G6PD deficiency
-Hemophilia A (factor VIII)
and B (factor IX).
-SCID (IL-receptor gamma-
chain deficiency)
a) Fragile X sdx (which is a
trinucleotide repeat disease
CGG (affected gene FMR-1
ch. X).
b) Hypophosphatemic rickets
Males 100% penetrance:
-Mental retardation
-Large ears
-Prominent jaw
-Macro-orquidism (usually
postpuberal)
Females 60% penetrance:
-Mental retardation
 MODE OF INHERITANCE
MITOCHONDRIAL
NOTE: this mutation can be
unevenly distributed into
daughter cells during cell
division; some cells may
inherit mire mitochondria in
which the normal DNA
predominates, while others
inherit mostly mitochondria
with the mutated disease-
causing
geneHETEROPLASMY------>
CHARACTHERISTICS
Looks like X-linked dominant
-Disease in every generation
-NO male to male
transmission
-Disease inherited only
maternally
-Highly aerobic tissues are
affected: neuropathies and
myopathies.
RECURRENT RISK:
-If father is affected 0% of
the children are affected.
-If mother is affected 100% of
children are affected.
EXAMPLES
-Leber hereditary optic
neuropathy
-MELAS: mitochondrial
encephalopathy, lactic
acidosis, and stroke-like
episodes.
-MERRM: myoclonic epilepsy
with ragged red muscle
fibers.
Clues for USMLE tricky
questions: possible answer
given for mitochondrial
inheritance:
-oxidative phosphorylation
pathway is affected (LEBER)
-Encodes 22 transfer RNAs
and 2 ribosomal RNAs.
-tRNA-lys-defect (MELAS)
-tRNA-leu-defect (MERRM)

AUTOSOMAL ANEUPLOIDY
Is a desviation from the euploid number, represents the gain (+) or loss (-) of a specific chromosome. Two major forms of
aneuploidy are observed:
a) Monosomy (loss of chromosome); inconsistent with live
b) Trisomy (gain of chromosome) 13,18 and 21; the most common cause of spontaneous loss of pregnancy (52% in
the first trimester).
*Triple screening for down syndrome (in utero): detect approximately 70% of fetuses
a) alfa-feto protein
b) Chorionic Gonadotropin
c) Unconjugated estriol
DISEASE KARYOTYPE HALLMARKS
Trisomy 21 -47,XY,+21 or -Mental retardation
Down Syndrome (+) -47,XX,+21 -Congenital heart defects (40%)
-Increase the risk of ALL
Due to : a) Non-disjunction in meiosis -Alzheimer disease by 5th or 6th decade
(95%) or (APP amyloid precursor protein in Ch
b) Robertsonian Translocation (5%) 21.

Trisomy 18 -47,XY,+18 or -Mental retardation

Edward Syndrome -47,XX,+18 -Congenital heart defects
*Very poor prognosis -Clenched fist with overlapping fingers
-Rocker-bottom feet
-Micrognathia and low-set ears.
Trisomy 13 -47,XY,+13 or -Mental retardation
Patau Syndrome -47,XX,+13 -Polydactyly
*Very poor prognosis -Cleft lip, palate
-Microphthalmia
-Microcephaly
 SEX CHROMOSOME ANEUPLOIDY
Is relatively common and tends to have less severe consequences than does autosomal
aneuploidy.
-At least one X Ch. Is required for survival
-If more than one X Ch is present; all but one will become Barr body in each cell.
-Numerical chromosomal aneuploidies are generally caused by Non dysjunction
-Mosaicism-tissues with genetically different cells
NOTE: down sdx and turner sdx mostly are numerical or structural alterations of
chromosomes.

Turner Syndrome (USMLE) -45,X (monosomy) 50% or -Short stature

-Females with 45,X;46,XY are
at increased risk for gonadal
blastoma
-Cystic higroma in utero
resulting in excess nuchal
skin and webbed neck.
Klinefelter Syndrome
-45,XO -Edema of wrists and ankles
in newborn
*IS THE ONLY ONE -Primary amenorrhea
MONOSOMY CONSISTENT -Coartation of the aorta or
WITH LIFE other congenital heart defect
otherwise
*Is an example of -Infertility
chromosomal deletion -Gonadal dysgenesis;
absence of ovarian functions
-47,XXY -Testicular atrophy
-Infertility
-Gynecomastia
-Low testosterone
-Female distribution of hair
-Elevated FSH and LH
-High-pitched voice

STRUCTURAL CHROMOSOMAL ABNORMALITIES

ABNORMALITY HALLMARKS
DELETIONS: occurs when a chromosome loses some of -Karyotype: 46,XX or 46,XY,del(5p)
its genetic information. -High-pitched, cat-like cry (due to under develop of
Can be: terminal deletions or interstitial deletions; larynx)
both result in: Cri-du-chat syndrome. -Mental retardation, microcephaly
-Congenital heart disease
MICRODELETIONS: can be read just with FISH Another examples may include micro deletions in
Examples include: several contiguous genes:
a) Prader-Willi sdx a) DiGeorge Syndrome; congenital absence of
b) Angelman sdx thymus and p/thyroids, hypocalcemic tetany,
c) Alfa-thalasemia T-cell immunodeficiency, characteristic facies
with cleft palate, heart defects.
b) Wilms tumor; (WAGR) Aniridia, Genital
abnormalities, Retardation.
c) Williams syndrome; hypercalcemia,
supravulvar aortic stenosis, mental
retardation.
 STRUCTURAL CHROMOSOMAL ABNORMALITIES
ABNORMALITY HALLMARKS
ISOCHROMOSOME: (always lethal in utero) is *The karyotype of an isochromosome for the
when a chromosome divides along the axis long arm of the X chromosome would be:
perpendicular to its normal axis of division. 46,X,i(Xq); this karyotype results in an
Most isochromosomes that have been individual with Turner Syndrome, indicating
observed in live births involve the X that most of the critical genes (22%)
Chromosome. responsible for that syndrome are on Xp.
USMLE pool of options for this question
(Turner Syndrome):
1) 78% have 45,X monosomy; due to
non-disjunction in MEIOSIS.
2) 22% have an isochromosome
46,X,i(Xq).
3) Mosaicism-45,X and 46,XX; due to
non-disjunction in MITOSIS.
Fluorescence in situ Hybridization (FISH): is useful just to detect numerical alterations of
chromosomes and NOT structural alterations; can detect:
a) Translocations
b) Aneuploidies
c) Deletions; including microdeletions.