Genetic Chromosome Abnormalities and Inheritance Notes

Genome structure and ploidy

• The human genome is composed of $2$ sets of chromosomes, with $23$ chromosomes per set, for a total of $46$ chromosomes in a typical human cell.
• Ploidy terminology:
  • Ploidy: refers to the number of chromosome copies per cell.
  • Euploidy: a normal complete set of chromosomes.
  • Aneuploidy: an abnormal set (gain or loss of chromosomes).
  • X and Y chromosome abnormalities are more common than autosomal abnormalities.
  • Polyploidy: multiple haploid copies of the genome; common in plants.

Chromosomal rearrangements and translocations

• Translocations/rearrangements involve a piece of one chromosome breaking off and attaching to another non-homologous chromosome.
• Reciprocal translocations:
  • Exchange of segments between two non-homologous chromosomes.
  • Can be balanced or unbalanced.
  • Balanced translocations are more common and involve exchange without net loss or gain of genetic material.
  • Example: Philadelphia chromosome – fusion of two genes:
  • ABL1 gene on chromosome $9$ fuses with BCR gene on chromosome $22$, creating a hybrid gene that can drive cancer.
• Unbalanced translocations:
  • Not a reciprocal exchange; can result in partial trisomies or monosomies or telomere acquisitions in cancer cells (somatic cells).
• Clinical significance of translocations:
  • Can contribute to cancers and fertility issues.
• Robertsonian translocations:
  • Fusion of two acrocentric chromosomes at the centromere, producing one large chromosome and one small chromosome.
  • The long arms (Q arms) fuse and short arms (p arms) are lost.
  • Confined to acrocentric chromosomes: $13,$14, $15,$21, $22$.
  • Carriers are usually normal, but offspring can have significant issues.
  • Karyotype often appears as $45$, reflecting the fusion.
  • Fertility issues may be present.
• Somatic translocations:
  • Occur in somatic (non-gamete) cells.
  • Can contribute to diseases such as chronic myelogenous leukemia (CML) with the Philadelphia chromosome.

Deletions and duplications

• Deletions/duplications are the most common type of structural variation after aneuploidies.
• Examples:
  • Cri-du-chat syndrome (deletion on the short arm of chromosome $5$, i.e., del(5p)).
  • 46,XX/XY with deletion at 5P (cri-du-chat).

Microdeletions and microduplications

• Small-scale genetic alterations that can affect individual genes or larger chromosome segments.
• Can disrupt gene function and lead to various genetic disorders.
• Charcot–Marie–Tooth (CMT) disease:
  • A hereditary peripheral nervous system condition with progressive distal muscle atrophy.
  • PMP22 gene is essential for myelin formation.
  • CMT1A (most common form): duplication of the PMP22 gene on chromosome $17$, leading to overexpression.
  • Hereditary neuropathy with liability to pressure palsies (HNPP): deletion of PMP22 leads to susceptibility to nerve damage under pressure.

Polyploidy

• Triploidy:
  • $3$ sets of chromosomes.
  • Incidence: $rac{1}{10000}$ births.
  • Outcome: typically dies shortly after birth.
  • Causes: dispermy — two sperm fertilize one egg; digynic or diandric origins.
  • Spontaneous abortion incidence for chromosomal abnormality: $rac{15}{100}$ (15%).
• Tetraploidy:
  • $4$ sets of chromosomes.
  • Rare at conception; if present, usually unviable post-fertilization.
  • Spontaneous abortion incidence: $rac{5}{100}$ (5%).

Aneuploidy

• Definition: abnormal number of chromosomes (gain or loss).
• Monosomy:
  • One chromosome is missing (e.g., monosomy of autosomes is typically not viable; sex chromosome monosomy (Turner syndrome) is viable).
  • Autosome monosomies are generally not compatible with life (per the transcript), whereas sex chromosome monosomies can be viable.
• Trisomy:
  • Three copies of a chromosome (type of aneuploidy).
  • Several trisomies are viable and some are relatively common.
  • Most common autosomal trisomies that are viable: $ext{Trisomy 13}, ext{Trisomy 18}, ext{Trisomy 21}.$
• Trisomy 21 (Down syndrome):
  • Most common viable trisomy.
  • Associated with intellectual disability, distinct facial features, and increased risk of leukemia; Alzheimer’s disease is a risk factor.
  • Incidence: rac{1}{800}-rac{1}{1000} births.
  • Characteristics:
  • Dysmorphic features
  • Hypotonia
  • 30–40% have structural heart defects
  • 15–20× increased risk for leukemia
  • More frequent respiratory infections
  • Variable intellectual disability (moderate to mild)
  • Mechanism: gene imbalance, with about 90 ext{%} of cases due to nondisjunction of maternal chromosomes.
  • Down syndrome and Alzheimer’s dementia: sobre aging risk, with 50% or more developing dementia as they age (not genetic for now).
• Trisomy 18 (Edwards syndrome):
  • Incidence: $rac{1}{6000}$ births.
  • >5% survive to term; 5–8% survive beyond 12 months.
  • Characteristics:
  • Distinctive facial features (small jaw, small ears, low-set teeth)
  • Overlapping fingers, rocker-bottom feet
  • 90% have congenital heart defects (e.g., VSD)
  • Severe cognitive impairment and developmental delay; degree varies.
• Trisomy 13 (Patau syndrome):
  • Incidence: rac{1}{16000}-rac{1}{20000} births.
  • About 5% survive the first year.
  • Distinct physical features: orofacial clefts, polydactyly, microcephaly, microphthalmia, CNS defects; 90% have cardiac defects.

Sex chromosome aneuploidy: incidence and features

• Incidence: about $rac{1}{1439}$ for X- and Y-chromosome abnormalities.
• Generally less severe than autosomal aneuploidies (except for X0 Turner syndrome).
• More compatible with life owing to X-inactivation and the relatively small Y chromosome with few genes.
• X-chromosome inactivation in females:
  • At any given time, only one X is active (XX in females or XY in males).
  • One X becomes inactivated during early embryogenesis; the inactivated X forms the Barr body.
  • The inactivation process is random; not all genes on the inactive X are silenced.
  • Requires the X inactivation center (Xic).
  • X-inactivation is regulated by the XIST gene, a non-coding RNA that acts in cis.
• Klinefelter syndrome (XXY):
  • Most common disorder causing male infertility.
  • Incidence: rac{1}{500}-rac{1}{1000} births.
  • Phenotype: taller stature, hypotonia; mild learning difficulties (verbal skills).
  • Intelligence in the normal range but often shy; 30% have gynecomastia; small testes; reduced facial/body hair.
  • May go undetected; typically sterile with hypogonadism.
  • Increased risk of osteoporosis, breast cancer, metabolic syndrome, cardiovascular disease.
  • Treatment: Testosterone therapy to enhance secondary sex characteristics.
• Turner syndrome (45, X or mosaic 45, X/46,XX):
  • Incidence: rac{1}{5000}-rac{1}{10000} births.
  • 50% are 45, X; 30–40% mosaic (45,X/46,XX); 10–20% involve deletion of Xp.
  • Female-only and characterized by partial or complete loss of one X chromosome.
  • Features: short stature, ovarian dysfunction, premature ovarian failure, lack of secondary sex characteristics, congenital heart defects.
  • Additional notes: normal intelligence is common but spatial perception may be diminished; 60–80% show absence of paternal X contribution in Turner patients.
  • Treatment: growth hormone therapy; estrogen replacement to induce secondary sex characteristics and maintain bone health; regular monitoring.
• Trisomy X (XXX):
  • Incidence: $rac{1}{1000}$ births.
  • Usually due to nondisjunction during meiosis; 95% maternal X.
  • Typically no physical abnormalities; mild reduction in intellectual skills; early intervention is recommended.
• XYY syndrome:
  • Incidence: $rac{1}{1000}$ births.
  • Extra Y chromosome in males; often taller stature; reduced IQ; speech development issues; increased incidence of ADD/ADHD; early intervention and educational support.
• Uniparental disomy (UPD):
  • UPD occurs when an individual receives two copies of a chromosome (or part of a chromosome) from one parent and no copies from the other parent.
  • Mechanisms include trisomic rescue, monosomic rescue, and postzygotic nondisjunction.
  • Examples:
  • Prader–Willi syndrome (PWS) and Angelman syndrome (AS)
  • Maternal UPD for chromosome $6$ and Maternal UPD for chromosome $21$.
  • Clinical implications:
  • Genomic imprinting disorders
  • Potential recessive diseases when two copies from the same parent carry the same recessive allele
  • Diagnosis/management: genetic testing and counseling.

Fluorescence in situ hybridization (FISH)

• Basic elements: DNA probe and target sequence.
• Probe labeling techniques:
  • Nick translation
  • Random primed labeling
  • PCR
• Labeling strategies:
  • Direct labeling (fluorophore) – faster and allows direct visualization.
  • Indirect labeling (hapten) – slower due to additional antibody steps but can provide enhanced signal via multiple antibody layers.

Pedigree charts, proband, and genetic testing

• Pedigree chart: a visual representation of a family’s genetic history.
• Proband: the first person in a family identified as having a genetic disorder or trait.
• Downsides of pedigree-only assessment:
  • Does not account for environmental factors.
• Genetic testing and counseling are often needed for accurate inheritance assessment.
• Autosomal inheritance: equal gender distribution; one generation may show disease without prior generation (possible autosomal recessive pattern).
• Cystic fibrosis (CF): autosomal recessive inheritance.
  • Requires two defective copies (one from each parent).
  • Carrier parents: each child has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected.
  • Population frequencies (approximate): Europeans $rac{1}{2500}$; African American $rac{1}{17000}$; Asian American $rac{1}{30000}$.
  • Roughly $2{,}000$ mutant variants identified.
  • Organs affected: liver (infection, inflammation, obstruction), sweat glands (elevated chloride in sweat), liver (cirrhosis), pancreas (exocrine dysfunction with diabetes and pancreatitis), intestine (neonatal obstruction and distal intestinal obstruction), exocrine insufficiency.
• Next-generation sequencing (NGS) evidence:
  • Can identify CNVs; clinical variant reports assist in autosomal recessive diseases.

Sickle cell disease (SCD)

• Autosomal recessive disorder characterized by production of abnormal hemoglobin (HbS) due to a point mutation in the HBB gene, which differs from the normal HBA/HB gene.
• The HbS mutation provides some protection against malaria in carriers (heterozygotes).
• Phenotype: codominance of two alleles; results in anemia, recurrent infections, acute vaso-occlusive pain crises, and functional asplenia (hypersplenism).

Autosomal dominant inheritance

• Both sexes equally affected; no skipping generations; no new carrier status in affected individuals.
• Detection: advances in sequencing (NGS) help identify CNVs; gene dosage can help construct pedigree risk.
• If one parent carries a defective allele, each child has a 50 ext{%} chance of inheriting the disorder.

Monogenic disorders by example and pattern

• Marfan syndrome: autosomal dominant; caused by mutation in the FBN1 gene; defective connective tissue.
  • Features include scoliosis, elongated limbs, severe pectus excavatum, skeletal, ocular, and cardiac involvement.
  • High risk of aortic dissection; complete penetrance; variable expressivity.
• Achondroplasia: autosomal dominant; mutation in FGFR3; impaired cartilage growth.
  • Homozygous state is lethal.
  • Physical: average trunk with short arms/legs; apnea; bowed legs; kyphosis; spinal stenosis.
  • 100% penetrant.
• X-linked inheritance overview:
  • Located on the X chromosome; genes can be dominant or recessive.
  • X-linked dominant disorders affect both sexes but are more severe in males.
  • X-linked recessive disorders more commonly affect males (e.g., hemophilia A, Duchenne muscular dystrophy).
  • Carrier females may be unaffected or mildly affected depending on lyonization and gene.
• X-linked dominant conditions and carrier females:
  • Carrier females may show a phenotype (dominant) or may be unaffected (recessive) depending on the gene.

X-chromosome inactivation and dosage compensation

• Typically one X chromosome is inactivated in each female cell; this creates a mosaic of active X chromosomes across tissues.
• XIST (X-inactive specific transcript) non-coding RNA regulates X inactivation; it acts in cis and is part of the X inactivation center (Xic).
• Barr body is the condensed, inactivated X chromosome in somatic cells.

Hypohidrotic ectodermal dysplasia (HED)

• Can be inherited by three different patterns:
  • X-linked recessive (EDA gene most cases)
  • Autosomal recessive (EDAR, EDARADD, or WNT10A)
  • Autosomal dominant (EDAR, EDARADD, or WNT10A)
• Deficiency impairs development of hair, sweat glands, and teeth.
• Females may display mosaicism for certain HED mutations due to X-inactivation.

Mosaicism

• Mosaicism: the presence of two or more cell populations with different genotypes in one individual, arising from a single fertilized egg.
• Chromosomal basis: some cells have different chromosome numbers or structural changes than others.
• Mechanisms include:
  • Chromosome nondisjunction
  • Anaphase lag
  • Mutations after fertilization

Mechanisms of aneuploidy and related concepts

• Nondisjunction: failure of chromosomes to separate properly during anaphase, leading to aneuploidies.
• Anaphase lag: a chromosome lags during cell division and is not included in one of the daughter nuclei, causing monosomy in that cell lineage.
• Prenatal and postnatal implications include the spectrum of chromosomal disorders described above.

Down syndrome recap and facial/clinical features

• Down syndrome (Trisomy 21) features include:
  • Dysmorphic facial features and hypotonia
  • Microbrachycephaly and flat occiput; low-set ears; flat nasal bridge; epicanthal folds; loose nape skin
  • Brachydactyly; single palmar crease; clinodactyly; Brushfield spots
  • Early-onset Alzheimer’s disease risk in aging individuals
• Life expectancy data in the transcript:
  • About 50{%} live to age $50$, 44{%} to $60$, 14{%} to $70$ (indicative lifetime expectancy ranges in historical cohorts; note that modern data have improved outcomes).
• The condition is largely due to nondisjunction of maternal chromosomes in most cases (around 90{%}).

Additional notes on karyotyping and CNVs

• Karyotyping detects chromosome number and structure; modern methods also detect copy number variations (CNVs) via bioinformatic pipelines.
• Karyotyping remains the best available method to determine chromosome number.
• CNVs contribute to phenotypic variability and can be detected using array-based or sequencing-based approaches.

References to auxiliary disorders and features

• Williams syndrome (7q11.23 deletion):
  • Noted as an example of a microdeletion syndrome.
• Charcot–Marie–Tooth disease (CMT) and PMP22:
  • PMP22 duplication causes CMT1A; PMP22 deletion causes HNPP.
• Cystic fibrosis (CF): autosomal recessive; signature genes, organs affected, and carrier risk discussed above.
• Sickle cell disease (SCD): autosomal recessive; homozygous HbS mutation in HBB; codominance with heterozygotes; malaria resistance in carriers.
• X-linked conditions summary:
  • Hemophilia A (F8 gene) – X-linked recessive, with spontaneous mutation events in about $1{,} ext{3}$ of cases and no family history.
  • Duchenne muscular dystrophy (DMD) – X-linked recessive.
  • Rett syndrome and Fragile X – X-linked dominant patterns.

Quick reference: key numeric facts (for exam familiarity)

• Chromosome sets: $2$ sets, $23$ per set → $46$ total
• Philadelphia chromosome example uses chr$9$ and chr$22$
• Trisomies with viable births: $13, 18, 21$; Down syndrome incidence roughly rac{1}{800}-rac{1}{1000} per birth
• Trisomy 18 incidence: $rac{1}{6000}$; >5 ext{%} survive to term; 5-8 ext{%} survive beyond 12 months
• Trisomy 13 incidence: rac{1}{16000}-rac{1}{20000}; ~5 ext{%} survive first year
• Sex chromosome aneuploidy incidence: about $rac{1}{1439}$; Turner/tet/xxx/xxy/xyy patterns with various penetrances
• Turner syndrome incidence: rac{1}{5000}-rac{1}{10000}; 45, X is common
• Klinefelter incidence: rac{1}{500}-rac{1}{1000}; XXY
• Trisomy X and XYY: $rac{1}{1000}$ each
• Uniparental disomy possibilities include imprinting disorders such as PWS and AS and UPD for chromosome $6$ and $21$
• Cystic fibrosis carrier frequencies vary by population; common European frequency around $1/2500$; others vary
• Autosomal dominant examples include Marfan syndrome and Achondroplasia; penetrance and expressivity noted
• X-inactivation results in Barr bodies; XIST RNA is central to inactivation
• Mosaicism concept and mechanisms include nondisjunction and anaphase lag

End of notes