Chapter 2

1. The Human Genome and Its Chromosomes

 DNA Structure: A Brief Review DNA is a polymeric nucleic acid composed of a

deoxyribose (five-carbon sugar), a phosphate group, and a nitrogen-containing
base. There are two purines (adenine and guanine) and two pyrimidines (thymine
and cytosine). Nucleotides polymerize into long chains via 5′-3′ phosphodiester
bonds. As established by Watson and Crick in 1953, DNA exists as a double helix
where two antiparallel chains are held together by hydrogen bonds: A pairs with T,
and G pairs with C. This complementary nature allows for precise replication and
repair.

 Organization of Human Chromosomes The nuclear genome consists of 46 DNA

molecules (one for each chromosome), totaling over 6 billion nucleotides. DNA is
packaged as chromatin through complexes with basic proteins called histones. Two
copies of histones H2A, H2B, H3, and H4 form an octamer, around which ~140 base
pairs (bp) of DNA wind to form a nucleosome. These "beads on a string" are
compacted into a 30-nm-diameter solenoid fiber, which represents the fundamental
unit of chromatin organization. Solenoids are further packed into loops of ~100 kb
attached to a protein scaffold.

 Organization of the Human Genome The genome is functionally organized into

gene-rich and gene-poor regions. Of the 3 billion base pairs, less than 1.5% actually
encodes proteins, and only about 5% contains regulatory elements. The genome
contains an estimated 25,000 genes.

 The Mitochondrial Chromosome A small but vital portion of the genome resides in
the mitochondria in the cytoplasm. This chromosome is a circular molecule only 16
kb in length—less than 0.03% of the smallest nuclear chromosome. It encodes 37
genes and exhibits exclusively maternal inheritance.

 Single-Copy DNA Sequences This makes up at least half of the genome. While it
contains most of the 25,000 genes, the protein-coding portions (exons) are only a
small fraction of all single-copy DNA. Much of its remaining function is still being
studied.

 Repetitive DNA Sequences Repetitive DNA is categorized by its distribution:

o Satellite DNA (Tandem Repeats): These are short repeats organized head-to-
tail, making up 10-15% of the genome. For example, $\alpha$-satellite DNA
(171-bp units) is found at centromeres and is critical for chromosome
segregation.

o Dispersed Repeats: Two major families are medically important: Alu family
(~300 bp, >1 million copies, 10% of DNA) and LINE (L1) family (~6 kb, 850,000
 copies, 20% of DNA). Both have been implicated as causes of mutation in
hereditary diseases.

o Segmental Duplications: Duplicated segments spanning hundreds of kb that

account for at least 5% of the genome and can mediate rearrangements
leading to disease.

2. Cell Division

 The Cell Cycle The cycle consists of Interphase and Mitosis. Interphase includes:

o G1: No DNA synthesis; cells can enter a non-dividing G0 phase.

o S Phase: DNA synthesis; each chromosome replicates to form two sister

chromatids held at the centromere.

o G2: A brief stage where the cell prepares for division. Checkpoints monitor
the accuracy of DNA synthesis and spindle attachment; if damage is too great,
the cell undergoes apoptosis (programmed cell death).

 Mitosis Mitosis is somatic cell division resulting in two daughter cells with identical
46-chromosome complements (diploid/2n). It has five stages:

1. Prophase: Chromosomes condense and centrosomes move to poles.

2. Prometaphase: Nuclear membrane breaks down; chromosomes attach to

spindle microtubules via kinetochores.

3. Metaphase: Chromosomes reach maximal condensation and align at the

equatorial plane.

4. Anaphase: Sister chromatids separate and move to opposite poles.

5. Telophase: Chromosomes decondense; nuclear membranes reform. Mitosis

concludes with cytokinesis (cytoplasm cleavage).

 The Human Karyotype A karyotype is the standard chromosome complement of an

individual. Chromosomes are identified by length and the location of the
centromere, which divides the chromosome into a short arm (p) and a long arm (q).
G-banding (Giemsa staining) is the most common clinical method, creating
characteristic patterns of dark and light bands.

 Meiosis Meiosis is a unique division in germline cells that results in gametes with
only 23 chromosomes (haploid/n). It consists of one round of DNA synthesis
followed by two rounds of division.

 First and Second Meiotic Division

 o Meiosis I (Reduction Division): Chromosome number is halved. Prophase I is
complex, involving Leptotene, Zygotene (synapsis/pairing), Pachytene
(crossing over/recombination), Diplotene (chiasmata visible), and Diakinesis.
In Anaphase I, homologous chromosomes move to opposite poles
(disjunction).

o Meiosis II: Follows Meiosis I without DNA replication. Sister chromatids

separate (like mitosis), resulting in four haploid cells.

3. Human Gametogenesis and Fertilization

 Spermatogenesis This process begins at puberty and takes approximately 64 days to

complete. Spermatogonia undergo mitosis, then primary spermatocytes undergo
Meiosis I to form secondary spermatocytes. These undergo Meiosis II to form
spermatids, which differentiate into sperm without further division. A male produces
an estimated $10^{12}$ sperm in a lifetime.

 Oogenesis This begins prenatally. By the third month of fetal development, oogonia
become primary oocytes. They are arrested in Prophase I for years until ovulation.
Just before ovulation, Meiosis I completes, producing a secondary oocyte and the
first polar body. Meiosis II begins and halts at metaphase II, completing only if
fertilization occurs, yielding a mature ovum and a second polar body.

 Fertilization Occurs in the fallopian tube within a day of ovulation. The penetration of
a single sperm triggers the completion of Meiosis II. The resulting diploid zygote
begins a series of cleavage divisions (mitoses) to initiate embryonic development.

4. Medical Relevance of Mitosis and Meiosis

The biological significance of these processes is to ensure the constancy of chromosome

number and genome integrity.

 Meiotic Relevance: Meiotic nondisjunction (failure of chromosomes to separate

properly) is the most common mutational mechanism in humans. It causes
aneuploidy (abnormal chromosome number), a leading cause of developmental
defects and mental retardation.

 Mitotic Relevance: Mitotic nondisjunction after fertilization can lead to

chromosomal mosaicism. Furthermore, abnormal chromosome segregation in
rapidly dividing somatic cells is a key step in the development of many tumors and
cancers.

Chapter 3
1. Monogenic versus Multifactorial Inheritance

 Monogenic (Mendelian) Inheritance: Characters whose presence or absence

depends on the genotype at a single locus. While no character is entirely
programmed by a single gene pair, monogenic traits have a specific genotype that is
both necessary and sufficient for expression.

 Multifactorial Inheritance: Most human characters are governed by genes at more

than one locus (polygenic) and often interact with environmental factors. These are
called complex or multifactorial.

 Categories of Characters:

o Dichotomous: Characters you either have or do not have (e.g., extra fingers).

o Continuous (Quantitative): Measured traits like height or weight, often

controlled by quantitative trait loci (QTLs).

2. Mendelian Pedigree Patterns

There are five archetypal patterns of Mendelian inheritance determined by whether the
gene is on an autosome or sex chromosome:

 Autosomal Dominant: Appears in every generation; affected individuals usually have

an affected parent.

 Autosomal Recessive: Usually seen only in the sibship of the proband; parents are
typically unaffected carriers.

 X-linked Dominant: Twice as common in females; affected males pass it to all

daughters but no sons.

 X-linked Recessive: Affects mainly males; transmitted through healthy carrier

females.

 Y-linked: Affects only males; affected fathers pass it to all sons.

3. X-Inactivation (Lyonization)

In early female embryogenesis, one X chromosome in each cell is randomly and permanently
inactivated to ensure dosage compensation (balancing gene expression between XX females
and XY males). The inactivated X appears as a Barr body (sex chromatin) in interphase
nuclei.

4. Mosaicism due to X-Inactivation

Because the choice of which X is inactivated is random and occurs early, females are mosaics
of two cell populations—one expressing the paternal X and one expressing the maternal X.
  Manifesting Heterozygotes: Occasionally, a carrier of an X-linked recessive condition
(like Duchenne muscular dystrophy) shows symptoms if "bad luck" leads to the
mutant X being active in a critical proportion of cells.

5. Genes on the Y Chromosome

The Y chromosome contains few genes, mostly related to male sexual function (like the SRY
gene). Deletions in the long arm of the Y are a significant cause of male infertility.

6. Genes in the Pseudoautosomal Region

Small segments at the distal ends of X and Y chromosomes (Xp/Yp and Xq/Yq) contain
homologous DNA that pairs and recombines during male meiosis. Genes here (like SHOX)
segregate like autosomes, showing male-to-male transmission, despite being on sex
chromosomes.

7. Conditions Caused by Mutation in Mitochondrial DNA

 Maternal Inheritance: Mitochondria are inherited exclusively from the mother

because sperm do not contribute mitochondria to the zygote.

 Heteroplasmy: A cell can contain a mixed population of normal and mutant

mitochondrial genomes. The severity of the disease depends on the proportion of
mutant genomes.

 Genetic Bottleneck: During oogenesis, the number of mitochondria is restricted and

then amplified, which can cause wide variation in the proportion of mutant DNA
passed to offspring.

8. Ambiguity in Single Pedigrees

Because human families are small, it is rarely possible to define the mode of inheritance
unambiguously from one pedigree. Observed ratios of affected to unaffected children often
deviate from expected Mendelian ratios due to chance or bias of ascertainment.

9. Getting the Right Ratios: Bias of Ascertainment

If families are only identified because they have at least one affected child, unaffected
families are missed. In two-child families of carrier parents, the expected ratio of affected
children isn't 1 in 4, but actually 8 in 14 because families with zero affected children are not
counted.

10. Mendelian Characters and Gene Sequences

Mendelian characters are abstract entities. A character defined by pedigree analysis might
not correspond to a single functional DNA unit; for example, some "genes" encode non-
translated RNAs rather than proteins.

11. Heterogeneity
  Locus Heterogeneity: The same clinical phenotype results from mutations at
different loci (e.g., different genes causing deafness).

 Allelic Heterogeneity: Different mutations within the same gene cause the disease in
different patients.

 Clinical (Phenotypic) Heterogeneity: Different mutations in the same gene produce

entirely different diseases (e.g., HPRT mutations causing either gout or Lesch-Nyhan
syndrome).

12. Complications to Basic Mendelian Pedigree Patterns

 Common Recessive mimicking Dominant: If a recessive trait (like blood group O) is

common, it may appear in successive generations due to repeated matings with
carriers.

 Non-penetrance: A person with the genotype fails to show the phenotype. This is
common in dominant conditions and is often age-related (e.g., Huntington disease).

 Variable Expression: Different family members show different features or severities

of the same syndrome (e.g., Waardenburg syndrome).

 Anticipation: A condition becomes more severe or has an earlier onset in successive

generations, usually caused by unstable repeat expansions (e.g., Fragile X, Myotonic
dystrophy).

 Imprinting: Expression depends on which parent transmitted the gene. For example,
glomus body tumors manifest only when inherited from the father.

 Male Lethality: In some X-linked dominant conditions (like Incontinentia pigmenti),

affected males abort spontaneously, so the condition is seen only in females.

 Inbreeding: Increases the incidence of rare recessive conditions and can cause X-
linked recessive traits to appear in females if an affected man marries a carrier
woman.

 New Mutation and Mosaicism: A severe dominant condition may appear without a
family history due to a fresh mutation. If a mutation occurs after fertilization, the
individual is a mosaic.

13. Mosaics and Chimeras

 Mosaics: Derived from a single zygote but contain two or more genetically different
cell lines.

 Chimeras: Result from the fusion of two zygotes into a single embryo (the reverse of
twinning).

14. Genetics of Multifactorial Characters

  Polygenic Theory: Large numbers of independent genetic and environmental factors
create a normal (Gaussian) distribution in the population.

 Regression to the Mean: Offspring of parents with extreme phenotypes tend to be

closer to the population average.

 Heritability ($h^2$): The proportion of total variation in a trait caused by genetic

differences.

 Threshold Model: For dichotomous characters (like cleft palate), an underlying

continuous susceptibility exists; an individual is affected only if they exceed a certain
threshold.

15. Factors Affecting Gene Frequency

The Hardy-Weinberg relationship ($p^2 + 2pq + q^2 = 1$) relates gene frequencies to
genotype frequencies in a population. Departures from this equilibrium are caused by:

 Non-random mating (Inbreeding and Consanguinity).

 Selection (Natural selection removing disadvantageous alleles).

 Mutation (Fresh mutations replacing lost alleles).

 Heterozygote Advantage: When carriers have a selective advantage (e.g., cystic

fibrosis carriers being resistant to typhoid fever).
 Chapter 5: Principles of Clinical Cytogenetics
1. Introduction to Cytogenetics

Clinical cytogenetics focuses on identifying microscopically visible changes in chromosome

number or structure, known as chromosome disorders, which account for 1% of live births
and 50% of first-trimester spontaneous abortions.

 Clinical Indications for Analysis: Cytogenetic study is required for patients with early
growth problems (developmental delay, mental retardation, ambiguous genitalia),
stillbirth or neonatal death (where incidence is ~10%), fertility problems (recurrent
miscarriage), a family history of abnormalities, or neoplasia. It is also standard for
pregnancies at advanced maternal age (over 35 years).

 Chromosome Identification: Standard analysis usually involves T lymphocytes from

peripheral blood, which are stimulated to divide and then arrested in metaphase.

o Banding Techniques: G-banding (Giemsa) is the standard method, producing

light and dark bands that correspond to DNA base composition. Q-banding
uses fluorescence to identify variants called heteromorphisms in satellite
DNA. R-banding is the reverse of G-banding and is standard in some
European laboratories.

o Special Procedures: C-banding specifically stains centromeric

heterochromatin. High-Resolution Banding uses chromosomes in prophase
or prometaphase to reveal 550 to 850+ bands for precise diagnosis. Fragile
Sites are non-staining gaps, such as the one associated with Fragile X
syndrome.

 Fluorescence In Situ Hybridization (FISH): This molecular technique uses glowing

DNA probes to detect the presence, absence, or location of specific sequences. It can
be performed on interphase cells, allowing for rapid prenatal screening of
chromosomes 13, 18, 21, X, and Y. Spectral karyotyping (SKY) allows all 24
chromosomes to be "painted" in different colors simultaneously.

 Microarrays (Array CGH): This genomic approach measures relative DNA copy
number across the entire genome. While it offers high resolution for detecting
deletions and duplications, it cannot detect balanced rearrangements like
translocations.

2. Chromosome Abnormalities

 Abnormalities of Chromosome Number:

o Heteroploid refers to any number other than 46; Euploid is an exact multiple
of the haploid number (n=23).
 o Polyploidy: Triploidy (3n=69) usually results from fertilization by two sperm
(dispermy); Tetraploidy (4n=92) results from failure of early zygotic cleavage.

o Aneuploidy: The most common abnormality, usually resulting from meiotic

nondisjunction (failure of chromosomes to separate). Trisomy (three copies)
for chromosomes 13, 18, or 21 is viable because these autosomes have the
lowest gene content. Monosomy (one copy) is usually lethal, with the
exception of Turner syndrome (45,X).

 Abnormalities of Chromosome Structure: These result from chromosome breakage

followed by abnormal reconstitution.

o Unbalanced Rearrangements: These involve a gain or loss of genetic material,

often leading to an abnormal phenotype due to haploinsufficiency. Examples
include deletions (terminal or interstitial), duplications (partial trisomy), and
isochromosomes (one arm missing, the other duplicated). Ring
chromosomes occur when both ends of a chromosome break and join; they
are often mitotically unstable. Dicentric chromosomes contain two
centromeres and may be stable if one centromere is inactivated
(pseudodicentric).

o Balanced Rearrangements: The chromosomal material is present but

rearranged.

 Inversions: Paracentric (excludes centromere) or Pericentric (includes

centromere). They usually do not affect the carrier but increase the
risk of producing unbalanced offspring.

 Translocations: Reciprocal translocations involve segment exchange

between non-homologous chromosomes. Robertsonian
translocations involve the fusion of two acrocentric chromosomes
(13, 14, 15, 21, 22) near the centromere with loss of the short arms.
Insertions are nonreciprocal translocations requiring three breaks.

3. Mosaicism

Mosaicism is the presence of two or more different chromosome complements in an

individual derived from a single zygote. It is usually caused by postzygotic mitotic
nondisjunction. Individuals with mosaic Down syndrome or mosaic Turner syndrome are
often less severely affected than nonmosaic patients. Pseudomosaicism refers to mosaic
cells that arise in culture and do not reflect the individual's actual makeup.

4. Incidence of Chromosome Anomalies

 Live Births: The overall incidence is about 1 in 160 (0.7%). Common trisomies are 21,
18, and 13; sex chromosome aneuploidies include Klinefelter and Turner syndromes.
  Spontaneous Abortions: At least 40% to 50% of miscarriages have chromosome
abnormalities. 45,X is the most common single abnormality in abortuses, accounting
for ~20% of cases. Trisomy 16 is common in abortions but never seen in live births.

5. Parent-of-Origin Effects

 Genomic Imprinting: An epigenetic process where gene expression depends on

which parent transmitted the allele. It involves DNA methylation or histone
modifications.

 Prader-Willi and Angelman Syndromes: Both involve the 15q11-q13 region. Prader-
Willi (obesity, mental retardation) results from loss of the paternal contribution,
usually via deletion (~70%) or maternal uniparental disomy (UPD) (~30%). Angelman
(seizures, spasticity) results from loss of the maternal contribution, usually via
deletion (~70%), paternal UPD (~5%), or mutations in the UBE3A (E6-AP) gene.

 Other Imprinting Effects: UPD for chromosome 11p15 is associated with Beckwith-
Wiedemann syndrome. Complete hydatidiform moles are diploid and purely
paternal in origin, leading to abnormal placental growth without a fetus. Ovarian
teratomas are purely maternal in origin.

 Confined Placental Mosaicism: The placental karyotype is abnormal while the fetus
is normal. This can result in "trisomy rescue," where a trisomic cell loses a
chromosome to become euploid, potentially leading to uniparental disomy in the
fetus.

6. Studies in Human Meiosis

Retrospective studies show that maternal nondisjunction accounts for >90% of trisomy 21
and 100% of trisomy 16 cases. Direct sperm analysis via FISH shows disomy rates of 1 in
1000 to 2000. Intracytoplasmic sperm injection (ICSI) in IVF has been associated with a
sharp increase in sex chromosome abnormalities and imprinting defects.

7. Mendelian Disorders and Cancer

 Chromosome Instability Syndromes: Rare autosomal recessive disorders like Bloom

syndrome (high sister chromatid exchange) and ICF syndrome (centromeric
instability due to DNA methyltransferase deficiency).

 Cytogenetics in Cancer: Tumors often exhibit nonrandom chromosome changes.

Identifying these changes via FISH, SKY, or microarrays provides vital diagnostic and
prognostic information.
 Chapter 6: Clinical Cytogenetics:

Disorders of the Autosomes and the Sex Chromosomes

I. Autosomal Disorders

Autosomal disorders typically involve growth retardation, mental retardation, and multiple
congenital anomalies, with the severity determined by the specific genes and dosage
involved.

1. Down Syndrome (Trisomy 21)

Down syndrome is the most common genetic cause of moderate mental retardation,
affecting 1 in 800 live births.

 Phenotype: Characterized by hypotonia, short stature, brachycephaly (flat occiput),

flat nasal bridge, upslanting eyes with epicanthal folds, and short, broad hands with a
single transverse palmar crease.

 Medical Complications: One-third of infants have congenital heart disease. There is

also an increased risk for leukemia and the early onset of Alzheimer disease.

 Chromosomal Causes:

o Standard Trisomy 21 (95%): Caused by meiotic nondisjunction, usually in

maternal meiosis I.

o Robertsonian Translocation (4%): Usually involves chromosomes 14 or 22. It

shows no relation to maternal age but carries a high recurrence risk (10–15%
if the mother is the carrier).

o 21q21q Translocation: An isochromosome containing two 21q arms; all

offspring of a carrier will have Down syndrome or nonviable monosomy.

o Mosaic Down Syndrome (2%): A mix of normal and trisomy 21 cells, often
leading to a milder phenotype.

 Etiology: Strongly associated with increased maternal age and abnormal

recombination patterns during meiosis I.

2. Trisomy 18 and Trisomy 13

 Trisomy 18: Incidence is 1 in 7,500. Features include failure to thrive, severe heart
malformations, receding jaw, and a characteristic clenched fist with overlapping
digits.

 Trisomy 13: Incidence is 1 in 15,000 to 25,000. Characterized by severe CNS

malformations (holoprosencephaly), cleft lip/palate, polydactyly, and microphthalmia
(small eyes).
3. Autosomal Deletion Syndromes

 Cri du Chat (Deletion 5p): Affects 1 in 7,000 newborns. Notable for a mewing cat-like
cry due to deletion at 5p15.3 and severe mental retardation due to deletion at
5p15.2.

4. Genomic Disorders (Microdeletions and Duplications)

These are caused by unequal crossing over between repeated DNA sequences.

 Smith-Magenis Syndrome: Deletion at 17p11.2; duplication of this same region

causes a milder behavioral phenotype.

 CMT1A and HNLPP: Duplication of a 1.4 Mb region on 17p12 causes Charcot-Marie-

Tooth disease (nerve damage); deletion of the same region causes HNLPP.

 22q11.2 Deletion (DiGeorge/Velocardiofacial Syndrome): Affects 1 in 2,000 to

4,000. Causes craniofacial anomalies, heart defects (e.g., tetralogy of Fallot), and
mental retardation.

 Cat-Eye Syndrome: Results from tetrasomy (four copies) of the 22q11.2 region.

II. The Sex Chromosomes and Their Abnormalities

Sex chromosome disorders are generally less severe than autosomal ones due to X-
inactivation and the low gene content of the Y chromosome.

1. The Y Chromosome and Sex Determination

 SRY Gene: Located at Yp11.3, this "testis-determining factor" acts as the master
switch for male development.

 Spermatogenesis: Deletions in AZF regions (AZFa, b, or c) on Yq are major causes of

male infertility (azoospermia).

2. The X Chromosome and X-Inactivation

 Lyonization: One X is randomly silenced in females to equalize gene dosage with

males. However, 15% of genes escape inactivation, mostly on the short arm (Xp).

 XIST Gene: Located in the X inactivation center (Xq13.2), it produces a noncoding

RNA that initiates the silencing process.

 Nonrandom (Skewed) Inactivation: If an X chromosome is structurally abnormal, it is

preferentially inactivated to minimize genetic imbalance.

3. Common Sex Chromosome Aneuploidies

  Klinefelter Syndrome (47,XXY): Incidence is 1 in 1,000 males. Features include tall
stature, small testes, infertility, and learning difficulties.

 47,XYY Syndrome: Incidence is 1 in 1,000 males. Usually asymptomatic but

associated with tall stature and an increased risk of ADHD.

 Trisomy X (47,XXX): Incidence is 1 in 1,000 females. Often undiagnosed; features

include tall stature and potential learning problems.

 Turner Syndrome (45,X): Incidence is 1 in 4,000 females. Features include short

stature, webbed neck, "streak" ovaries (causing infertility), and lymphedema at birth.

III. Disorders of Gonadal and Sexual Development

These conditions occur when genes involved in the sexual differentiation pathway are
mutated or missing.

 Gonadal Dysgenesis: XY females can result from an excess of the DAX1 gene (via
duplication), which suppresses SRY, or from mutations in SOX9 (associated with
camptomelic dysplasia).

 Female Pseudohermaphroditism: Usually caused by Congenital Adrenal Hyperplasia

(CAH) due to 21-hydroxylase deficiency (1 in 12,500). Excess androgens cause
masculinized genitalia in 46,XX infants.

 Male Pseudohermaphroditism:

o 5$\alpha$-reductase deficiency: Prevents the conversion of testosterone to

dihydrotestosterone, leading to feminized external genitalia in 46,XY males.

o Androgen Insensitivity Syndrome (AIS): A 46,XY individual has a completely

female phenotype due to mutations in the androgen receptor gene, making
target cells unresponsive to male hormones.
 Chapter 7: Patterns of Single-Gene Inheritance

I. Overview and Concepts

 Variation in Genes: A locus is the specific position of a gene on a chromosome.

Alleles are alternative versions of a gene at a locus; the most common version is the
wild-type or common allele. A haplotype is a set of alleles at a cluster of loci on a
single chromosome. Polymorphism occurs when at least two common alleles exist at
a locus in a population.

 Genotype and Phenotype: The genotype is an individual's genetic constitution, while

the phenotype is the observable expression (clinical, cellular, or biochemical).
Pleiotropy refers to a single gene defect producing multiple diverse phenotypic
effects in different organ systems.

 Zygosity:

o Homozygous: Identical alleles at a locus.

o Heterozygous: Different alleles at a locus.

o Compound Heterozygote: Two different mutant alleles of the same gene are
present.

o Hemizygous: A male with a single abnormal allele on the X chromosome.

 Pedigrees and Fitness: A pedigree is a graphical representation of a family tree

(kindred); the proband is the affected member who first brings the family to medical
attention. Fitness is a measure of the impact of a condition on reproduction,
specifically the number of offspring an affected individual has who survive to
reproductive age compared to a control group.

II. Mendelian Inheritance

 Chromosomal Location: Inheritance patterns are determined by whether the gene is

autosomal (chromosomes 1-22) or X-linked.

 Dominant and Recessive: A phenotype is recessive if expressed only in homozygotes

and dominant if expressed in both homozygotes and heterozygotes. Codominance is
the expression of two different alleles (e.g., ABO blood groups). Incomplete
dominance occurs when the phenotype is more severe in homozygotes than in
heterozygotes (most human dominant disorders fall into this category).

III. Factors Affecting Pedigree Patterns

 Penetrance and Expressivity: Penetrance is the probability (all-or-none) that a

genotype will show any phenotypic expression; reduced penetrance means some
individuals with the genotype show no symptoms. Expressivity is the degree of
severity of the phenotype among those who are affected.
  Neurofibromatosis 1 (NF1): Demonstrates variable expressivity (some have only skin
spots, others have life-threatening tumors) and age-dependent penetrance
(symptoms develop over time).

 Split-Hand Deformity: An example of an autosomal dominant trait with reduced

penetrance (about 70%), often causing the disorder to appear to "skip" generations.

 Age at Onset: Some disorders are congenital (present at birth), while others are late-
onset, manifesting only in adult life (e.g., Huntington disease).

IV. Correlating Genotype and Phenotype (Heterogeneity)

 Allelic Heterogeneity: Different mutations at the same locus (e.g., nearly 1400
different mutations in the CFTR gene for cystic fibrosis).

 Locus Heterogeneity: Mutations at different loci cause the same phenotype (e.g.,
retinitis pigmentosa is caused by mutations at over 43 different loci).

 Phenotypic (Clinical) Heterogeneity: Different mutations in the same gene produce

strikingly different diseases (e.g., LMNA mutations can cause progeria, muscular
dystrophy, or lipodystrophy).

V. Autosomal Patterns of Mendelian Inheritance

 Autosomal Recessive (AR):

o Characteristics: Typically seen only in the sibship of the proband; parents are
usually healthy carriers; recurrence risk for sibs is 1 in 4 (25%).

o Sex-Influenced: AR disorders like hemochromatosis are more common in

males due to lower iron loss compared to menstruating females.

o Carrier Frequency: Most mutant alleles for AR disorders are "hidden" in

carriers; for Cystic Fibrosis, ~98% of mutant alleles are in carriers.

o Consanguinity and Inbreeding: Mating between relatives increases the risk of

AR disorders. Identity by descent is measured by the coefficient of
inbreeding (F); for first cousins, F = 1/16.

o Genetic Isolates: Small populations (e.g., Ashkenazi Jews) may have high
frequencies of specific rare alleles like Tay-Sachs.

 Autosomal Dominant (AD):

o Characteristics: Appears in every generation; any child of an affected parent

has a 50% risk.

o Pure vs. Incomplete Dominance: Pure dominance is rare; most AD disorders

like Achondroplasia are incompletely dominant, where homozygotes are
much more severely affected (often lethal) than heterozygotes.
 o Fitness: There is an inverse relationship between reproductive fitness and the
proportion of cases due to new mutations (if fitness is 0, all cases are new
mutations).

o Sex-Limited: Expressed in only one sex despite being autosomal (e.g., male-
limited precocious puberty).

VI. X-Linked Inheritance

 X Inactivation: Random silencing of one X in female cells to ensure dosage

compensation. This results in females being mosaics of two cell populations.

 X-Linked Recessive:

o Patterns: Affects mainly males; transmitted by carrier females; no male-to-

male transmission.

o Hemophilia A: Classic example; daughters of affected males are all carriers;

sons of carrier females have a 50% risk.

o Manifesting Heterozygotes: A carrier female may show symptoms if skewed

X-inactivation leads to the mutant X being active in a critical proportion of
cells.

 X-Linked Dominant:

o Patterns: Twice as common in females; all daughters and no sons of an

affected male are affected.

o Male Lethality: Some conditions are lethal in hemizygous males (e.g., Rett
syndrome), meaning they are seen almost exclusively in females.

 New Mutation: High frequency in X-linked lethal disorders like Duchenne Muscular
Dystrophy (DMD) to replace alleles lost when affected males do not reproduce.

VII. Pseudoautosomal Inheritance

 Genes in the distal pairing regions of X and Y (e.g., the SHOX gene) recombine like
autosomes, allowing for male-to-male transmission despite being on sex
chromosomes.

VIII. Mosaicism

 Somatic Mosaicism: Results in segmental manifestations of a disease (e.g.,

segmental NF1) if the mutation occurred after conception in a somatic lineage.

 Germline (Gonadal) Mosaicism: A parent has a clone of mutant cells in their

germline but not their somatic tissues; this explains how two affected children can be
born to apparently normal parents (e.g., seen in ~6% of lethal osteogenesis
imperfecta cases).
IX. Imprinting in Pedigrees

 Mechanism: Expression of a phenotype depends on the sex of the transmitting

parent.

 Albright Hereditary Osteodystrophy (AHO): If the GNAS mutation is inherited from

the mother, the child gets AHO plus pseudohypoparathyroidism (PHP1a); if
inherited from the father, the child gets AHO only (PPHP) because the GNAS gene is
imprinted only in certain renal tissues.

X. Unstable Repeat Expansions

 Anticipation: The tendency of some conditions to become more severe or have an

earlier onset in successive generations.

 Polyglutamine Disorders (Huntington disease): CAG expansion in the coding region;

larger expansions correlate with earlier onset; shows paternal transmission bias for
massive expansions.

 Fragile X Syndrome: CGG expansion in the 5' untranslated region; premutations (60-
200 repeats) can expand to full mutations (>200) only in female gametogenesis.

 Myotonic Dystrophy: CTG expansion in the 3' untranslated region; massive

expansions causing congenital DM occur only in female gametogenesis.

 Friedreich Ataxia: Unique because it is autosomal recessive; involves an AAG

expansion within an intron.

XI. Mimics and Mitochondrial Inheritance

 Mimics: Teratogens or shared environmental exposures can simulate Mendelian

patterns. Segmental aneusomies (contiguous gene syndromes) involve dosage
changes of multiple genes that segregate like single alleles.

 Maternal Inheritance (Mitochondrial Genome):

o Mechanism: mtDNA is inherited exclusively from the mother.

o Heteroplasmy: A cell contains a mix of normal and mutant mtDNA; disease

manifests when mutant DNA exceeds a certain threshold.

o Genetic Bottleneck: The restriction and amplification of mtDNA during

oogenesis leads to wide variation in mutant loads among offspring.