13.2 Chromosomal Basis of Inherited Disorders

Chromosomal Abnormalities and Disorders

Chromosomal abnormalities occur when something goes wrong with the number or structure of chromosomes, and these changes can have serious effects on human health and development. Understanding how these abnormalities arise and what they cause is essential for genetic counseling, diagnosis, and interpreting karyograms in the lab.

Karyogram Interpretation for Abnormalities

A karyogram (also called a karyotype) is a visual display of an individual's chromosomes arranged in homologous pairs. To create one, cells are collected during metaphase (when chromosomes are most condensed and visible), then stained, photographed, and arranged by size, centromere position, and banding pattern.

Karyograms can reveal two broad categories of chromosomal abnormalities:

• Numerical abnormalities: changes in chromosome number, such as aneuploidy (one extra or one missing chromosome) or polyploidy (entire extra sets of chromosomes)
• Structural abnormalities: changes in chromosome structure, including deletions, duplications, inversions, or translocations

When you look at a karyogram, you're checking whether all 23 pairs are present and whether any chromosomes look unusual in size, shape, or banding.

Nondisjunction and Aneuploidy Disorders

Nondisjunction is the failure of chromosomes to separate properly during cell division. This is the most common cause of aneuploidy.

• During meiosis I, homologous chromosomes fail to separate
• During meiosis II, sister chromatids fail to separate

Either way, the result is gametes with an abnormal number of chromosomes. When one of these gametes is fertilized, the offspring ends up with too many or too few chromosomes.

Aneuploidy refers to having an abnormal chromosome number in a cell:

• Monosomy: one chromosome is missing from a pair ($2n - 1$)
• Trisomy: one extra chromosome is present in a pair ($2n + 1$)

The major aneuploidy disorders you should know:

• Down syndrome (trisomy 21)
• Edwards syndrome (trisomy 18)
• Patau syndrome (trisomy 13)
• Turner syndrome (monosomy X)
• Klinefelter syndrome (XXY)

Most autosomal monosomies and many trisomies are lethal before birth. The trisomies listed above are among the few that can survive to term, and even then, trisomy 18 and 13 carry very low life expectancy.

Effects of Chromosomal Structural Changes

Structural abnormalities happen when parts of chromosomes break and rejoin incorrectly. There are four main types:

• Deletions: a segment of a chromosome is lost entirely
• Duplications: a segment is copied, so extra copies exist
• Inversions: a segment breaks off and reattaches in the reverse orientation
  • Paracentric inversions do not include the centromere
  • Pericentric inversions include the centromere
• Translocations: genetic material is exchanged between non-homologous chromosomes
  • Reciprocal translocations involve a two-way swap of segments
  • Robertsonian translocations involve the fusion of two acrocentric chromosomes at their centromeres

These structural changes can affect the organism in several ways:

• Gene disruption: if a breakpoint falls within a gene, that gene may lose function
• Gene dosage effects: deletions or duplications change how many copies of a gene are present, which alters expression levels
• Position effects: moving a gene to a new location can place it near different regulatory elements, changing when or how much it's expressed
• Fusion genes: translocations can join parts of two different genes, creating a novel protein with altered function

A person can be a balanced carrier of a structural change, meaning they have no net gain or loss of genetic material and may appear phenotypically normal. However, during meiosis, their chromosomes may segregate unevenly, producing unbalanced gametes. This leads to increased risk of miscarriage, stillbirth, or offspring with congenital anomalies, and it can reduce the carrier's fertility.

Comparison of Chromosomal Disorders

Here's a closer look at the specific disorders and their characteristics:

Down syndrome (trisomy 21) results from an extra copy of chromosome 21, usually caused by nondisjunction during meiosis. Phenotypic effects include intellectual disability, characteristic facial features (upward-slanting eyes, flat nasal bridge), heart defects, and increased risk of leukemia and early-onset Alzheimer's disease. This is the most common viable autosomal trisomy.

Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) both result from nondisjunction producing an extra copy of chromosome 18 or 13, respectively. Both cause severe intellectual disability, multiple congenital anomalies (cleft lip/palate, heart defects), and very low life expectancy. Most affected infants do not survive past the first year.

Turner syndrome (monosomy X) occurs in females who have only one X chromosome (45,X). Phenotypic effects include short stature, ovarian dysfunction (often leading to infertility), webbed neck, heart defects, and some learning difficulties. This is the only viable monosomy in humans.

Klinefelter syndrome (47,XXY) occurs in males who carry an extra X chromosome. Phenotypic effects include tall stature, gynecomastia (breast tissue development), reduced fertility, and language or learning difficulties. Many individuals are not diagnosed until puberty or later.

Cri-du-chat syndrome (5p deletion) is caused by a deletion on the short arm of chromosome 5. It's named for the high-pitched cry of affected infants, which sounds like a cat's meow. Other effects include intellectual disability, microcephaly (abnormally small head), and heart defects.

Chromosomal Basis of Inherited Disorders

Genetic Basis and Inheritance

• Heredity is the passing of traits from parents to offspring through genes
• The genome (complete set of genetic material) is organized into chromosomes
• Chromosomes contain genes, and different versions of a gene are called alleles
• Mutations (changes in DNA sequence) can produce new alleles or, on a larger scale, cause chromosomal abnormalities
• Cytogenetics is the branch of genetics focused on studying chromosomes and their role in heredity and disorders

Genetic Counseling and Diagnosis

Genetic counseling provides information and support to individuals or families affected by or at risk for genetic disorders. Here's what the process typically involves:

1. Risk assessment: The counselor evaluates family history and medical records to estimate the likelihood of a chromosomal or genetic condition.
2. Education: The counselor explains inheritance patterns, what specific disorders involve, and what test results mean.
3. Testing options: Prenatal tests (such as amniocentesis or chorionic villus sampling) can detect chromosomal abnormalities before birth. Genetic testing can also identify carriers of recessive disorders or individuals at risk for dominant conditions.
4. Decision support: The counselor helps families understand their options without directing their choices.

Genetic counseling is especially relevant when a family has a history of chromosomal disorders, when parents are carriers of balanced translocations, or when maternal age increases the risk of nondisjunction events.