• Complex multigenic disorders are also called multifactorial or polygenic disorders.
• They result from interaction between:
  • multiple genetic variants
  • environmental factors
• A genetic variant present in at least 1% of the population is called a polymorphism.
• According to the common disease–common variant hypothesis:
  • many common polymorphisms are inherited together
  • each has only a small effect
  • each usually has low penetrance
  • together they increase disease risk
• Different polymorphisms do not contribute equally.
• Example: in type 1 diabetes, many genes are involved, but only a few contribute most of the risk.
• Certain HLA alleles account for more than 50% of the genetic risk.
• Some polymorphisms:
  • are shared by several related diseases
  • while others are specific to one disease
• Many disease-associated polymorphisms occur in noncoding DNA.
• Therefore, they may alter epigenetic regulation and gene expression, rather than directly changing protein structure.
• Multigenic inheritance also controls many normal traits, including:
  • hair color
  • eye color
  • skin color
  • height
  • intelligence
• These traits show continuous variation among individuals.
• Environmental factors strongly modify how multigenic traits are expressed.
• Example:
  • Type 2 diabetes has a strong genetic component.
  • Weight gain and obesity may reveal or worsen the underlying genetic tendency.
  • Thus:
    genetic susceptibility + obesity/environment → clinical diabetes
• A disorder should be called multigenic only after careful evaluation.
• Important clues include:
  • familial clustering
  • absence of a clear Mendelian inheritance pattern
  • absence of a chromosomal abnormality
  • variable severity among affected individuals
• However, variable severity alone is not enough, because reduced penetrance and variable expressivity can also occur in single-gene disorders.

KEY CONCEPT

• Multigenic disease = many genes + environment working together.
• Polymorphism = common genetic variant present in ≥1% of the population.
• Each variant usually has a small effect, but many together can produce significant disease risk.
• Environment can unmask genetic susceptibility.

CONCEPTUAL EXAMPLES

• Many diabetes-risk genes + obesity → type 2 diabetes becomes clinically apparent.
• Several HLA-related variants together → increased risk of type 1 diabetes.
• Multiple genes + environment → continuous traits such as height or skin color.

CYTOGENETIC DISORDERS

• Cytogenetic disorders result from abnormalities in the number or structure of chromosomes.
• They may involve:
  • autosomes
  • sex chromosomes
• Chromosomal abnormalities are relatively common:
  • about 1 in 200 newborns has some chromosomal abnormality
  • frequency is much higher in fetuses that do not survive to term
  • up to 50% of first-trimester spontaneous abortions may involve a chromosomal abnormality
• Karyotyping is a basic method used to study chromosomes.
• A karyotype = digital arrangement of stained chromosomes from a metaphase cell, organized from largest to smallest.
• Chromosomes can be stained using different techniques.
• The commonly used Giemsa stain (G-banding) produces a characteristic pattern of:
  • alternating dark bands
  • alternating light bands
    on each chromosome (Fig. 4.17).
• Each chromosome has its own characteristic banding pattern.
• Therefore, G-banding helps:
  • identify individual chromosomes
  • detect structural chromosome abnormalities
  • locate abnormalities that are large enough to alter the normal banding pattern

KEY CONCEPT

• Cytogenetic disorder = abnormal chromosome number or structure.
• Karyotype = metaphase chromosomes arranged by decreasing size.
• G-banding = characteristic light/dark chromosome pattern used for identification and detection of large structural abnormalities.

CONCEPTUAL EXAMPLES

• Extra or missing chromosome → numerical chromosomal abnormality.
• Missing or rearranged chromosome segment → structural abnormality.
• Abnormal G-band pattern on karyotype → helps identify the affected chromosome and region.

Numeric Abnormalities

• Normal human diploid cells contain 46 chromosomes:
  • 22 pairs of autosomes
  • 1 pair of sex chromosomes
  • Written as 2n = 46
• Haploid number (n) = one complete chromosome set.
• Any exact multiple of n is called euploid.
• More than two complete chromosome sets are called polyploid:
  • 3n = triploidy
  • 4n = tetraploidy
• In fetuses, polyploidy usually leads to spontaneous abortion.
• Aneuploidy = chromosome number that is not an exact multiple of n.
• The major cause of aneuploidy is nondisjunction → chromosomes fail to separate normally.
• Nondisjunction may occur during:
  • Meiosis I → homologous chromosomes fail to separate.
  • Meiosis II → sister chromatids fail to separate.
  • Mitosis → sister chromatids fail to separate in somatic cells.
• Anaphase lag can also cause aneuploidy:
  • one chromosome fails to move properly during cell division
  • → it is lost from one daughter cell.
• If nondisjunction occurs during meiosis, abnormal gametes may contain:
  • n + 1 → one extra chromosome
  • n − 1 → one chromosome missing
• After fertilization with a normal gamete:
  • (n + 1) + n = 2n + 1 → trisomy
    • one extra chromosome
  • (n − 1) + n = 2n − 1 → monosomy
    • one chromosome missing
• Autosomal monosomy is incompatible with life.
• Some autosomal trisomies can survive to birth.
• Trisomy 21 may allow survival into adulthood.
• Monosomy involving a sex chromosome can also be compatible with survival to birth.
• Mosaicism = one individual has two or more cell populations with different chromosome complements.
• Mosaicism can result from postzygotic mitotic nondisjunction:
  • one daughter cell becomes trisomic
  • another becomes monosomic
  • their descendants form different cell populations in the same person.
• Mosaicism involving sex chromosomes is relatively common, whereas autosomal mosaicism is less common.

KEY CONCEPT

• Euploid = complete chromosome sets.
• Polyploid = extra complete sets, such as 3n or 4n.
• Aneuploid = extra or missing individual chromosome.
• Nondisjunction → abnormal chromosome separation → trisomy or monosomy.
• Mosaicism = genetically different chromosome populations within one individual.

CONCEPTUAL EXAMPLES

• Normal cell → 2n = 46.
• Gamete receives one extra chromosome → n + 1 → after fertilization → 2n + 1 = trisomy.
• Gamete loses one chromosome → n − 1 → after fertilization → 2n − 1 = monosomy.
• Nondisjunction after fertilization → some cells normal and others abnormal → mosaicism.

Structural Abnormalities

• Structural chromosome abnormalities usually result from:
  chromosome breakage → loss or rearrangement of genetic material.
• Cytogenetic shorthand:
  • p = short arm of chromosome
  • q = long arm
  • Regions and bands are numbered from the centromere outward (Fig. 4.17).
  • Example: 2q34 = chromosome 2 → long arm (q) → region 3 → band 4.
• Major chromosome rearrangements after breakage are shown in Fig. 4.18.
• Translocation:
  • Part of one chromosome is transferred to another chromosome.
  • Usually reciprocal → two chromosomes exchange fragments.
  • Example: 46,XX,t(2;5)(q31;p14) means:
    • female with 46 chromosomes
    • reciprocal translocation between chromosomes 2 and 5
    • chromosome 2 breaks at q31
    • chromosome 5 breaks at p14
  • Balanced reciprocal translocation:
    • all genetic material is still present
    • carrier is usually normal unless a breakpoint disrupts an important gene
    • during gamete formation → unbalanced gametes may form → abnormal offspring
  • Robertsonian translocation:
    • occurs between two acrocentric chromosomes
    • breaks occur near centromeres
    • produces one large chromosome + one very small chromosome
    • small chromosome is lost → carrier has 45 chromosomes
    • loss is usually tolerated because acrocentric short arms contain highly repetitive genes
    • however, abnormal gametes may form → affected offspring
• Isochromosome:
  • abnormal chromosome ends up with two identical arms:
    • two p arms, or
    • two q arms
  • The acentric abnormal chromosome is lost.
  • Most common live-born example → i(Xq).
  • If fertilization also provides a normal X:
    • genes on Xp → monosomy
    • genes on Xq → trisomy
• Deletion:
  • loss of part of a chromosome.
  • One break → loss of a terminal segment.
  • Two breaks → loss of an internal segment.
  • Lost fragment usually lacks a centromere → disappears → genes are lost.
• Inversion:
  • two chromosome breaks occur
  • released segment turns around
  • rejoins in the opposite orientation.
• Ring chromosome:
  • a form of deletion
  • chromosome ends are lost
  • remaining ends join together → ring-shaped chromosome.

KEY CONCEPT

• Translocation = chromosome material moves/exchanges.
• Robertsonian = fusion of two acrocentric chromosomes → usually 45 chromosomes in carrier.
• Isochromosome = two identical arms.
• Deletion = chromosome segment lost.
• Inversion = segment reversed.
• Ring chromosome = both ends lost → chromosome forms a ring.

CONCEPTUAL EXAMPLES

• Two chromosomes exchange pieces but no DNA is lost → balanced translocation.
• Balanced carrier makes an abnormal gamete → child may receive too much or too little chromosome material.
• Chromosome loses an internal piece → deletion.
• Broken segment turns 180° and rejoins → inversion.
• Chromosome loses both ends and joins into a circle → ring chromosome.

FIG. 4.17 & 4.18 — CHROMOSOME BANDING + CHROMOSOMAL REARRANGEMENTS

🧠 Simplest idea

Chromosome breaks → pieces may be exchanged, lost, reversed, duplicated, or joined abnormally.

FIG. 4.17 — KARYOTYPE + X-CHROMOSOME BANDING

1️⃣ Karyotype

The chromosomes are arranged as:

1 → 22 + X/Y

This image shows a male karyotype = 46,XY.

• Chromosomes 1–22 = autosomes
• X and Y = sex chromosomes

2️⃣ X chromosome: p arm and q arm

• p = short arm
• q = long arm
• Gray constricted center = centromere

🧠 Memory:

p = petit = short

3️⃣ Region → Band → Subband

The chromosome is divided from the centromere outward.

Example:

Xq23

means:

X chromosome
→ q arm
→ region 2
→ band 3

If another decimal/subband is given:

Xq23.1
→ subband 1 within band 3.

Easy idea:

Chromosome → arm → region → band → subband

FIG. 4.18 — TYPES OF CHROMOSOMAL REARRANGEMENTS

1️⃣ TRANSLOCATION

A. Balanced reciprocal translocation

🔵 chromosome + 🩷 chromosome break.

Pieces are exchanged.

Chromosome A gives piece to B
↔
Chromosome B gives piece to A

Result:

Usually no net DNA loss or gain.

➡️ Called balanced reciprocal translocation.

🧠 Memory:
Balanced = exchange, but total material preserved

B. Centric fusion

Two chromosomes fuse around the centromeric region.

Small fragments may be:

lost

➡️ This is the basic idea of a Robertsonian-type translocation.

2️⃣ ISOCHROMOSOME

Normally a chromosome has:

one p arm + one q arm

In an isochromosome, abnormal centromere division produces:

• two identical p arms
  or
• two identical q arms

Result:

One arm is duplicated and the other is lost.

🧠 Memory:
Iso = same arms

3️⃣ DELETION

A chromosome breaks at two points.

The intervening piece is removed.

Result:

DNA fragment lost

➡️ chromosome becomes shorter.

🧠 Memory:
Deletion = DNA missing

4️⃣ INVERSION

A chromosome segment breaks off, turns 180°, and reinserts.

A. Paracentric inversion

The inverted segment does NOT include the centromere.

B. Pericentric inversion

The inverted segment DOES include the centromere.

🧠 Memory:

PARA = away from centromere
PERI = around centromere

5️⃣ RING CHROMOSOME

Both ends of a chromosome break.

The terminal fragments are lost.

The remaining ends join together.

⬇️

Ring chromosome

🧠 Easy flow:

Break both ends → lose tips → ends fuse → RING

🎨 COLOR / ARROW GUIDE

• 🔵 Blue chromosome = one chromosome
• 🩷 Pink chromosome = another chromosome
• 🟨 Arrows = direction of rearrangement
• 🔺 Orange triangles = break points
• Bracketed small pieces = lost fragments
• Gray circle = centromere

⭐ Fastest exam recall

Translocation = exchange
Deletion = loss
Inversion = segment flipped
Isochromosome = two same arms
Ring = chromosome ends join

🧠 One-line memory

BREAK → exchange, lose, flip, duplicate same arm, or make a ring.

General Features of Chromosomal Disorders

• Chromosomal disorders may result from:
  • loss of genetic material → deletion or monosomy
  • gain of genetic material → trisomy
  • rearrangement → translocation
• In general, loss of chromosomal material causes more severe abnormalities than gain.
• Extra chromosomal material may involve:
  • a whole chromosome → trisomy
  • part of a chromosome → e.g., Robertsonian translocation
• Abnormalities of sex chromosomes are usually better tolerated than similar abnormalities of autosomes.
• Sex chromosome disorders may cause only subtle changes and may not be recognized at birth.
• Infertility may become apparent only during adolescence.
• Most chromosomal disorders arise de novo:
  • parents are usually unaffected
  • recurrence risk in siblings is usually low
• An important exception is translocation Down syndrome, which may be inherited.

Cytogenetic Disorders Involving Autosomes

• Important autosomal abnormalities include:
  • trisomy 21
  • trisomy 18
  • trisomy 13
  • deletion involving 22q

Trisomy 21 (Down Syndrome)

• Down syndrome results from an extra copy of chromosome 21 and is the most common chromosomal disorder (Fig. 4.19).
• About 95% of affected individuals have complete trisomy 21:
  • chromosome number = 47
  • most commonly caused by meiotic nondisjunction
• In these cases, the parents are usually unaffected.
• Maternal age strongly increases risk:
  • younger than 20 years → about 1 in 1550 live births
  • older than 45 years → about 1 in 25
• In about 95% of cases, the extra chromosome 21 is of maternal origin.
• The reason aging increases meiotic nondisjunction in the ovum is not fully understood.
• About 4% of cases result from translocation of chromosome 21 material to chromosome 14 or 22.
• These cases may be familial.
• A parent may be a healthy carrier of a Robertsonian translocation.
• About 1% of patients are mosaics:
  • mixture of 46-chromosome and 47-chromosome cells
  • caused by mitotic nondisjunction early in embryonic development
  • manifestations are often milder and depend on the proportion of abnormal cells
• Typical physical features are usually recognizable at birth:
  • flat facial profile
  • oblique palpebral fissures
  • epicanthic folds (Fig. 4.19)
• Down syndrome is an important cause of intellectual disability.
• About 80% have IQ values of approximately 25–50.
• Some mosaic patients may have much milder changes and near-average intelligence.
• About 40% have congenital heart disease, especially:
  • endocardial cushion defects
  • atrial septal defects
  • atrioventricular valve abnormalities
  • ventricular septal defects
• Cardiac abnormalities are a major cause of death in infancy and early childhood.
• Other congenital abnormalities include:
  • esophageal atresia
  • small-bowel atresia
• Children with trisomy 21 have a 10–20 times greater risk of acute leukemia:
  • acute lymphoblastic leukemia
  • acute myeloid leukemia
• Nearly all patients older than 40 years develop neuropathologic changes characteristic of Alzheimer disease.
• Abnormal immune responses increase susceptibility to:
  • serious infections, especially pulmonary infections
  • thyroid autoimmunity
• Other increased abnormalities include:
  • intestinal stenosis
  • Hirschsprung disease
  • cataracts and refractive errors
  • hearing loss
  • slow growth
  • cryptorchidism
  • hypospadias
• Improved medical care has increased survival.
• The source text gives a median age at death of about 60 years.
• The exact molecular mechanism remains uncertain.
• Increased dosage of chromosome 21 genes may contribute.
• One implicated gene is the amyloid-β precursor gene, related to Alzheimer disease.
• microRNAs and long noncoding RNAs may also contribute.
• Prenatal screening may include:
  • ↑ β-hCG
  • ↓ pregnancy-associated plasma protein A (PAPP-A)
  • ultrasound assessment of nuchal folds
• PAPP-A is produced by the syncytiotrophoblast, and a low level suggests poor placental function.
• Cell-free fetal DNA can also be detected in maternal blood.
• About 5%–10% of total cell-free DNA in maternal blood is fetal in origin.
• Next-generation sequencing can measure the amount of chromosome 21 DNA → provides a sensitive, specific noninvasive prenatal screening method.
• In the source text, positive screening results are confirmed by conventional cytogenetic analysis of fetal cells obtained by amniocentesis.

KEY CONCEPT

• Down syndrome = extra chromosome 21.
• Main mechanisms:
  95% meiotic nondisjunction + 4% translocation + 1% mosaicism.
• Increasing maternal age → increasing risk.
• Major associations:
  intellectual disability + congenital heart disease + leukemia + early Alzheimer-type changes + infections.
• Mosaic Down syndrome is generally milder.
• Prenatal screening → β-hCG, PAPP-A, nuchal assessment, and cell-free fetal DNA.

CONCEPTUAL EXAMPLES

• Chromosome 21 fails to separate during maternal meiosis → ovum receives an extra chromosome 21 → fertilization → trisomy 21.
• Healthy parent carries a Robertsonian translocation → abnormal chromosome 21 material passed to child → translocation Down syndrome.
• Nondisjunction occurs after fertilization → some cells have 46 chromosomes and others 47 → mosaic Down syndrome.
• Extra chromosome 21 gene dosage → contributes to the characteristic multisystem abnormalities of Down syndrome.

22q11.2 Deletion Syndrome

• 22q11.2 deletion syndrome results from a small interstitial deletion of chromosome 22 at band q11.2.
• It produces a variable combination of:
  • congenital heart disease, especially outflow-tract defects
  • palatal abnormalities
  • characteristic facial abnormalities
  • developmental delay
  • thymic hypoplasia → impaired T-cell immunity
  • parathyroid hypoplasia → hypocalcemia
• These manifestations were previously separated into:
  • DiGeorge syndrome
  • velocardiofacial syndrome
• Both are now recognized as part of the 22q11.2 deletion syndrome.
• Different sizes and positions of the deletion help explain the variable clinical presentation.
• When T-cell immunodeficiency + hypocalcemia dominate → DiGeorge syndrome.
• When facial abnormalities + cardiac defects dominate, with milder immunodeficiency → velocardiofacial syndrome.
• Patients also have an increased risk of psychiatric disorders:
  • schizophrenia
  • bipolar disorder
• About 25% of affected adults develop schizophrenia.
• Conversely, 22q11.2 deletions occur in about 2%–3% of individuals with childhood-onset schizophrenia.
• The exact molecular mechanism is not fully understood because the deleted region contains many genes, including:
  • protein-coding genes
  • noncoding regulatory RNAs
• Clinical findings may suggest the diagnosis, but confirmation requires detection of the deletion, typically by fluorescence in situ hybridization (FISH).

KEY CONCEPT

• 22q11.2 deletion → heart + palate + face + thymus + parathyroids + developmental abnormalities.
• DiGeorge pattern → thymic hypoplasia → ↓ T cells + parathyroid hypoplasia → hypocalcemia.
• Velocardiofacial pattern → prominent facial/palatal + cardiac abnormalities with milder immune deficiency.
• Diagnosis → FISH detection of the deletion.

CONCEPTUAL EXAMPLES

• Thymus underdeveloped → fewer functional T cells → impaired cellular immunity.
• Parathyroids underdeveloped → hypocalcemia.
• Same 22q11.2 deletion with different extent → one patient may mainly show DiGeorge features, while another mainly shows velocardiofacial features.

Cytogenetic Disorders Involving Sex Chromosomes

• Sex chromosome abnormalities are better tolerated than autosomal abnormalities.
• Karyotypes ranging from 45,X to 49,XXXXY may be compatible with life.
• Even males with two or three Y chromosomes have been identified.
• This tolerance mainly occurs because of:
  • X-chromosome inactivation (lyonization)
  • the relatively small amount of genetic information on the Y chromosome
• Lyonization means that in females, only one X chromosome remains genetically active in each cell.
• X inactivation begins early in fetal life, about 16 days after conception.
• In each embryonic cell:
  • either the maternal X or
  • the paternal X
    is randomly inactivated.
• Once an X chromosome is inactivated:
  same X remains inactive in all daughter cells.
• All X chromosomes except one are inactivated.
• Therefore, even a female with 48,XXXX has only one active X chromosome.
• This prevents females from receiving a double dose of X-linked gene products compared with males.
• Because X inactivation is random, females are mosaics:
  • some cells have the maternal X active
  • other cells have the paternal X active
• X inactivation is controlled by XIST, a gene producing a long noncoding RNA.
• XIST RNA:
  coats the X chromosome from which it is produced → silences genes on that chromosome.
• On the active X chromosome:
  • the XIST allele is switched off
  • genes remain active
• X inactivation is not complete.
• About:
  • 30% of genes on Xp
  • 3% of genes on Xq
    escape inactivation.
• These escaping genes are important in disorders such as Turner syndrome.
• Extra Y chromosomes are relatively well tolerated because the Y chromosome carries comparatively little genetic information.
• Most known Y-linked information is related to male differentiation.
• According to the source, the presence of a Y chromosome determines the male phenotype.
• The key gene is SRY (sex-determining region of Y), located on the short arm of the Y chromosome.
• Two important sex chromosome disorders discussed next are:
  • Klinefelter syndrome
  • Turner syndrome

KEY CONCEPT

• Sex chromosome abnormalities are better tolerated than autosomal abnormalities.
• Lyonization = all X chromosomes except one are inactivated.
• XIST RNA → coats and silences the inactive X chromosome.
• Females are cellular mosaics for maternal vs paternal X activity.
• Some X-linked genes escape inactivation, especially on Xp.
• SRY on Y chromosome → male differentiation.

CONCEPTUAL EXAMPLES

• Female cell randomly inactivates maternal X → all daughter cells from it keep the maternal X inactive.
• Another cell inactivates paternal X → its descendants keep the paternal X inactive.
• Thus one female contains two cell populations → X-chromosome mosaicism.
• Extra X chromosomes are mostly silenced → explains why multiple X chromosomes may still be compatible with life.