Genetic Diseases: Quick Reference

Basis for Genetic Disease

Mutations are permanent, heritable changes in the DNA sequence of nucleotides (cytosine, thymine, adenine, or guanine), which are the building blocks of DNA. These alterations can disrupt the normal function of genes, leading to the development of genetic diseases by affecting protein production or function.

Types of Mutations

Mutations are broadly classified into two categories. Single-gene (or Mendelian) mutations affect a single gene and include:

• Base-pair substitutions: A single nucleotide is replaced by another. These can be transitions (purine to purine or pyrimidine to pyrimidine) or transversions (purine to pyrimidine or vice versa). Depending on the location, these can cause missense (change in amino acid), nonsense (premature stop codon), or silent (no change in amino acid) mutations.
• Frameshift mutations: Involve the insertion or deletion of one or more nucleotides (not in multiples of three) within a gene sequence. This alters the reading frame of the mRNA during protein synthesis, often leading to a completely different protein product from the point of the mutation onward, or a premature stop codon.
  Chromosomal mutations involve larger-scale alterations, affecting the structure or number of entire chromosomes.

Gene Sequences

A gene is a segment of DNA that codes for a specific protein or functional RNA. Alleles are different versions or variants of the same gene, arising from slight differences in their DNA sequence. For example, a gene for eye color might have an allele for blue eyes and an allele for brown eyes. The locus (plural: loci) refers to the precise physical location or address on a chromosome where a specific gene or its allele is situated.

Homozygote and Heterozygote

In diploid organisms, somatic cells contain pairs of homologous chromosomes, one inherited from each parent. An individual is considered a homozygote for a particular gene if they possess two identical alleles (e.g., AA or aa) at the same locus on both homologous chromosomes. Conversely, an individual is a heterozygote if they possess two different alleles (e.g., Aa) at the same locus.

Dominant vs Recessive Alleles

Dominant alleles are those that express their associated trait or phenotype even when only one copy is present (i.e., in a heterozygote, Aa). The presence of the dominant allele masks the effect of the recessive allele. Recessive alleles, on the other hand, only manifest their associated trait or phenotype when two copies are present (i.e., in a homozygote, aa). In a heterozygote, the recessive allele is present but its effect is not typically observed.

Nomenclature

In genetic notation, a standard convention is followed to distinguish between dominant and recessive alleles. The uppercase letter (e.g., A) is always used to denote the dominant allele, while the corresponding lowercase letter (e.g., a) represents the recessive allele. This holds true irrespective of whether the dominant or recessive allele is responsible for a disease condition, providing a clear and consistent way to represent genotypes.

Overview of Genetic Diseases

Genetic diseases are medical conditions caused by abnormalities in an individual's DNA, often originating from mutations that disrupt the normal function of single genes or large-scale chromosomal structures. These diseases are heritable following distinct patterns: autosomal dominant, autosomal recessive, and X-linked, depending on the gene's location (autosome or sex chromosome) and its expression pattern.

Autosomal Dominant Inheritance

In autosomal dominant disorders, a single copy of a mutated allele located on an autosome (any non-sex chromosome) is sufficient to cause the disease phenotype. Affected individuals typically have one affected parent, and the trait appears in every generation without skipping. There is a $50\%$ chance for an affected heterozygous parent (Aa) to pass the mutated allele to each child, resulting in approximately half of their offspring being affected. When an individual inherits two copies of the dominant mutated allele (AA), the resulting disease is often much more severe, frequently leading to lethality or extreme clinical presentation, whereas heterozygous individuals (Aa) are affected with the characteristic disease phenotype.

Example - Achondroplasia and Marfan/Huntington's

Specific examples of autosomal dominant disorders include:

• Achondroplasia: A common form of dwarfism caused by a mutation in the $FGFR3$ gene, leading to abnormal cartilage growth and shortened long bones.
• Marfan syndrome: A connective tissue disorder resulting from mutations in the $FBN1$ gene, which encodes fibrillin-1, a component of elastic fibers. This affects the skeletal system, eyes, and cardiovascular system.
• Huntington’s disease: A progressive neurodegenerative disorder caused by an unstable expansion of CAG trinucleotide repeats in the huntingtin gene (HTT), leading to neuronal death in specific brain regions and manifesting as motor, cognitive, and psychiatric symptoms typically in adulthood.

Autosomal Recessive Inheritance

For autosomal recessive disorders, an individual must inherit two copies of the mutated allele (one from each parent) to express the disease. Parents of affected individuals are typically asymptomatic carriers (heterozygotes, Aa), each possessing one normal and one mutated allele. In such cases, there is a $25\%$ probability for each child to inherit two recessive alleles (aa) and be affected, a $50\%$ chance to be an asymptomatic carrier (Aa), and a $25\%$ chance to be completely unaffected (AA). These diseases often appear to skip generations, as carriers generally do not show symptoms. The risk of inheriting two copies of a rare recessive allele significantly increases with consanguinity, which is marriage or mating between closely related individuals, as they are more likely to share common ancestors and thus the same rare recessive alleles.

Examples

Key examples of autosomal recessive disorders include:

• Cystic fibrosis (CF): Caused by mutations in the $CFTR$ (cystic fibrosis transmembrane conductance regulator) gene, which codes for a chloride channel. This leads to the production of abnormally thick, sticky mucus that clogs organs, particularly the lungs and pancreas, resulting in respiratory and digestive problems.
• Sickle cell disease: A severe blood disorder resulting from a single nucleotide substitution (a point mutation of A to T) in the beta-globin gene, leading to an altered hemoglobin molecule (hemoglobin S). This causes red blood cells to become rigid and sickle-shaped under low oxygen conditions, obstructing blood flow and leading to anemia, pain crises, and organ damage.

Sex Chromosomes & X-linked inheritance

Human somatic cells typically contain 22 pairs of autosomes and one pair of sex chromosomes. Females usually have two X chromosomes (XX), while males have one X and one Y chromosome (XY). Genes located on the X chromosome follow X-linked patterns of inheritance, which differ from autosomal patterns, particularly for X-linked recessive disorders.

X-linked Recessive Inheritance

X-linked recessive inheritance patterns show a distinct sex predilection because males have only one X chromosome. If a male inherits a recessive mutated allele on his single X chromosome, he will express the disease (hemizygous). Females, with two X chromosomes, are typically carriers if they inherit one mutated allele, as the other healthy X chromosome often compensates; they usually only express the disease if they inherit two mutated alleles or if X-inactivation patterns are skewed. Affected males cannot pass the trait to their sons (as they pass a Y chromosome), but they will pass the mutated X to all their daughters, making them carriers. Skipped generations are common, particularly for females who may be asymptomatic carriers.

Examples

Prominent examples of X-linked recessive disorders include:

• Hemophilia A: A bleeding disorder caused by a deficiency in clotting Factor VIII, encoded by a gene on the X chromosome. Affected individuals experience prolonged bleeding after injury and spontaneous bleeding into joints and muscles.
• Duchenne muscular dystrophy (DMD): A severe, progressive muscle-wasting disease caused by mutations in the gene encoding dystrophin, a crucial protein for muscle fiber integrity. Males are primarily affected, experiencing muscle weakness and degeneration beginning in early childhood.

Chromosome Disorders

Chromosome disorders are conditions resulting from numerical or structural abnormalities in chromosomes, which are large structures carrying genetic information. A karyotype is a visual representation of an individual's complete set of chromosomes, arranged in homologous pairs and sized. It is a fundamental tool for diagnosing chromosomal abnormalities. The prevalence of clinically significant chromosome abnormalities is about $\frac{1}{150}$ live births. Chromosomal abnormalities are a major cause of reproductive loss, accounting for approximately $50\%$ of all spontaneous miscarriages. Furthermore, a substantial majority, approximately $95\%$, of conceptions affected by severe chromosome disorders are spontaneously aborted, highlighting the critical role chromosomes play in embryonic development.

Down Syndrome - Trisomy 21

Down syndrome is the most common autosomal aneuploidy in live-born infants, primarily caused by trisomy 21, meaning an individual has three copies of chromosome 21 instead of the usual two. This extra chromosome copy typically results from nondisjunction (failure of homologous chromosomes to separate during meiosis I or sister chromatids during meiosis II) during oogenesis or, less commonly, spermatogenesis, accounting for around $95\%$ of cases. The incidence of Down syndrome significantly increases with advanced maternal age, particularly after age 35. Prenatal diagnosis methods include:

• Amniocentesis: Performed around 16 weeks of gestation, involves sampling amniotic fluid for fetal cells.
• Chorionic Villus Sampling (CVS): Performed earlier, around 9–10 weeks, by sampling placental tissue.
• Quad Screen: A maternal blood test that measures four markers, providing a risk assessment rather than a definitive diagnosis.
  Key clinical characteristics of Down syndrome include global developmental delays (cognitive and motor), distinctive facial features (e.g., epicanthal folds, upward slanting eyes, flattened facial profile), congenital heart defects (present in about $50\%$ of cases), increased risk of certain medical conditions like leukemia, and susceptibility to premature aging and Alzheimer's disease.

Prenatal Diagnosis and Features Summary

For the diagnosis of chromosomal disorders, prenatal diagnostic options are crucial and include invasive procedures like amniocentesis and chorionic villus sampling (CVS) which provide definitive karyotype analysis, as well as non-invasive screening tests such as the Quad Screen. The definitive diagnosis relies on identifying characteristic features through clinical examination combined with a karyotype analysis, which visually confirms the chromosomal abnormality, such as the extra chromosome 21 in Down syndrome.

Chromosome Disorders: Other Aneuploidies

Beyond Trisomy 21, other forms of aneuploidy (abnormal number of chromosomes) exist.

• Autosomal Aneuploidy:
  • Monosomies (loss of one chromosome, e.g., 45,X for an autosome) are almost always lethal and generally incompatible with life.
  • Trisomies (gain of one chromosome, e.g., 47,XX,+18 for Trisomy 18 or Edwards syndrome; 47,XX,+13 for Trisomy 13 or Patau syndrome) can result in live births, though often with severe developmental abnormalities and reduced lifespan.
• Sex Chromosome Aneuploidy: These tend to be less severe than autosomal aneuploidies due to X-inactivation and the smaller genetic content of the Y chromosome.
  • Klinefelter syndrome (47,XXY): Affects males, typically characterized by tall stature, hypogonadism, infertility, and sometimes learning difficulties.
  • Turner syndrome (45,X): Affects females, characterized by short stature, ovarian dysgenesis (leading to infertility), heart defects, and webbed neck.
  • Triple X syndrome (47,XXX): Affects females, often asymptomatic or with minor developmental delays.
  • Jacob's syndrome (47,XYY): Affects males, often asymptomatic or with increased height and minor learning difficulties.

Recap: Key Concepts

• Mutations are permanent alterations in DNA nucleotide sequences (C, T, A, G) that form the molecular basis of genetic diseases, affecting gene function and protein production.
• Inheritance patterns dictate how genetic diseases are passed through families, primarily categorized as autosomal dominant (single mutated allele, no skipped generations, $50\%$ risk), autosomal recessive (two mutated alleles, only expressed in homozygotes, skipped generations, $25\%$ risk from carrier parents), and X-linked (genes on sex chromosomes, often disproportionately affecting males).
• Chromosome disorders involve large-scale numerical or structural changes in chromosomes, diagnosed through a karyotype analysis. They have significant prevalence in live births and are a major cause of miscarriages, with many affected conceptions spontaneously aborted.
• Down syndrome, specifically Trisomy 21, is the most prevalent autosomal aneuploidy, characterized by an extra chromosome 21 often due to nondisjunction. Its risk increases with maternal age, and it presents with distinct clinical features and is diagnosable via specific prenatal testing methods like amniocentesis and CVS.