Genetic Diseases - Basis for Genetic Disease and Inheritance

Basis for Genetic Disease

• Mutations are permanent changes in the sequence of nucleotides (C, T, A, or G) that form the genetic material. These are the basis of genetic diseases. (Reference: Fig. 2-1 in the transcript)

Overview

• Mutations provide the foundational basis for genetic diseases.

• They are permanent changes in DNA sequence.

Types of Mutations

• Single gene mutations

  • Base pair substitution (point mutation): one base pair is replaced by a different base.

  • Frameshift mutations:

  • Deletion of one base pair

  • Insertion of one base pair

• Normal base-pairing concept (for context): G pairs with C; A pairs with T (in DNA).

• Chromosomal mutations: changes at the chromosome level, affecting structure or number of chromosomes.

Gene Sequences

• Definitions

  • Alleles: different DNA sequences (versions) of the same gene.

  • Locus: the specific site on a chromosome where a given allele is located.

• Sources: information derived from educational resources (e.g., BBC static archive cited in the slides).

Gene Sequences: Genotype Terminology

• Chromosomes occur in paired sets in somatic (body) cells.

• Homozygote: an individual with matching alleles at the same locus on both chromosomes.

• Heterozygote: an individual with different alleles at the same locus on the paired chromosomes.

Nomenclature for Dominant and Recessive Alleles

• Dominant vs. Recessive Alleles

  • Dominant alleles need only one copy to be expressed in a heterozygote.

  • Recessive alleles require two copies to be expressed.

• Convention for gene notation

  • Uppercase letter denotes the dominant allele.

  • Lowercase letter denotes the recessive allele.

  • Example: A = dominant allele, a = recessive allele.

Practice and Review

• Today’s session is for practice; next class continues the concept review.

Autosomes vs Sex Chromosomes

• Genetic diseases can be located on autosomes or sex chromosomes.

• Autosomes: the 22 pairs of non-sex chromosomes.

• Sex chromosomes: X and Y chromosomes.

• Notation examples in slides show chromosomes numbered (e.g., 20, 17, 10, 12, 16, 18, 22) and sex chromosome designations (X, Y).

Autosomal Dominant Inheritance

• Basis: a single copy of the disease-causing allele is sufficient for expression in most cases.

• Pedigree pattern (example notation): Aa × aa results in offspring with approximately 50% affected (Aa) and 50% unaffected (aa).

• Key characteristics

  • On average, half of children with one affected parent are affected.

  • No skipped generations are typical (though exceptions occur due to reduced penetrance or small family size).

• Examples

  • Achondroplasia: caused by a mutation leading to changes in a protein essential for skeletal development.

  • Marfan syndrome: mutation in a gene coding for a collagen protein affecting elastic tissue.

  • Huntington’s disease: trinucleotide repeat disorder (CAGCAGCAG…) causing a change in a specific protein leading to brain cell death in adulthood; the function of that protein is still not fully understood.

• Genotype and phenotype considerations

  • Homozygous individuals (AA) generally have a more severe or often fatal condition than heterozygous individuals (Aa).

  • Heterozygous condition can still manifest disease in most autosomal dominant disorders shown in the examples above.

• Notable example details

  • Huntington’s disease described as a trinucleotide repeat disorder; an expanded CAG repeat alters a protein with unknown function.

Autosomal Recessive Inheritance

• Pedigree pattern: both parents must be carriers ( Aa × Aa ) to have affected offspring.

• Typical outcomes when both parents are carriers

  • 25% affected (aa)

  • 50% carriers ( Aa )

  • 25% unaffected non-carriers ( AA )

• Key characteristics

  • Affected individuals often cluster among siblings.

  • Skipped generations are common.

  • Consanguinity can increase the risk of autosomal recessive diseases.

• Examples

  • Cystic fibrosis: a mutation in a gene encoding a protein channel found in epithelial cells; results in thick mucus obstructing airways, pancreatic ducts, and other organs.

  • Sickle cell anemia (sickle cell disease): a single base pair mutation in the hemoglobin gene; RBCs become sickled under hypoxic or stress conditions.

• Phenotypic notes

  • Carriers are typically asymptomatic.

  • Affected individuals are homozygous recessive (aa).

Sex Chromosomes & X-linked Inheritance

• X-linked inheritance focuses on genes on the X chromosome.

• X-linked Recessive Inheritance (basis): XX, XY with X-linked alleles.

• Pedigree patterns

  • Male offspring are more frequently affected than female offspring.

  • Females can be carriers, while males usually express the disease if they inherit the mutant allele.

  • No transmission of an X-linked recessive disease from father to his sons (since fathers pass their Y chromosome to sons).

  • Skipped generations are common in females due to carrier status and X-inactivation dynamics.

• Examples

  • Hemophilia A: clotting factor deficiency (Factor VIII).

  • Hemophilia B: Factor IX deficiency (also X-linked).

  • Hemophilia C is autosomal recessive (not X-linked) despite similar naming.

  • Duchenne muscular dystrophy: mutation in the dystrophin gene on the X chromosome.

Chromosome Disorders

• Karyotype: a full set of an individual’s chromosomes; used for diagnostic purposes.

• Prevalence and impact

  • Chromosome abnormalities occur in about $rac{1}{150}$ live births.

  • About 50% of miscarriages have a major chromosome abnormality.

  • The vast majority (about 95%) of conceptions with chromosome disorders are spontaneously aborted.

• Down Syndrome (Trisomy 21)

  • Definition: presence of an extra copy of chromosome 21 (trisomy 21): 47,XX,+21 or 47,XY,+21.

  • Nondisjunction is responsible for ~95% of Down syndrome cases.

  • Maternal age effect: risk increases after age 35.

  • Prenatal diagnosis and screening: amniocentesis (around 16 weeks) and chorionic villus sampling (CVS) at 9–10 weeks; Quad Screen may be used as a less invasive preliminary assessment.

  • Karyotype example image: Down syndrome karyotype (described in slides).

• Down Syndrome: characteristics

  • Developmental delays

  • Distinct facial features

  • Congenital heart defects

  • Increased risk of leukemia

  • Premature aging

• Aneuploidy notes

  • Autosomal aneuploidy: monosomies are typically lethal; some trisomies survive.

• Sex Chromosome Aneuploidy

  • Turner syndrome: 45, X karyotype (monosomy X) – the only monosomy that is not universally lethal.

  • Klinefelter syndrome: 47, XXY karyotype.

  • XXX syndrome: 47, XXX karyotype.

  • XYY syndrome: 47, XYY karyotype.

Prenatal and Diagnostic Implications

• Prenatal testing options mentioned

  • Amniocentesis: typically performed around 16 weeks gestation.

  • Chorionic villus sampling (CVS): typically performed around 9–10 weeks gestation.

  • Prenatal Quad Screen: blood test to assess risk for certain conditions, potentially reducing the need for invasive testing.

Miscellaneous Notes and Concepts

• The terminology and concepts above are foundational for understanding genetic diseases, including the differences between autosomal and sex chromosome patterns, dominant vs recessive inheritance, and chromosomal abnormalities.

• Practical implications include family planning considerations, carrier testing, prenatal diagnosis, and the management of conditions with varying expressivity and penetrance.

• Ethical and practical implications include genetic counseling, screening decisions, and considerations around maternal age and reproductive choices.

$ext{Probability Examples (summary)}$

• Autosomal dominant, one affected parent (Aa × aa):

  • $P( ext{affected}) = rac{1}{2}$

• Autosomal recessive, both carrier parents (Aa × Aa):

  • $P( ext{affected}) = rac{1}{4}$

  • $P( ext{carrier}) = rac{1}{2}$

  • $P( ext{unaffected}) = rac{1}{4}$

• Down syndrome prevalence: approximately $rac{1}{150}$ live births, with ~95% due to nondisjunction.

• Chromosome disorders prevalence in conceptions: ~95% spontaneously aborted; ~50% miscarriages involve major chromosome abnormalities.

• Karyotype notations to remember: $45, X$ (Turner), $47, XXY$ (Klinefelter), $47, XXX$, $47, XYY$.

Key Terminology Recap

• Allele: different version of the same gene.

• Locus: specific site on a chromosome where a gene/allele is located.

• Homozygote: same allele on both chromosomes (e.g., AA or aa).

• Heterozygote: different alleles on the paired chromosomes (e.g., Aa).

• Pedigree: a family tree diagram used to track inheritance patterns.

• Nondisjunction: failure of chromosome pairs to separate properly during meiosis, leading to aneuploidies.

• Aneuploidy: abnormal number of chromosomes (e.g., monosomy or trisomy).

• Karyotype: full set of chromosomes used for diagnostic assessment.