Chromosomal Numerical Abnormalities

Chromosomal numerical abnormalities occur when there is a gain or loss of an entire chromosome.

• Also referred to as aneuploidy
• Involves all genes on the given chromosome
• Many human cancers are associated with chromosomal mutations.
• Typically occurs during mitosis or meiosis Meiosis The creation of eukaryotic gametes involves a DNA replication phase followed by 2 cellular division stages: meiosis I and meiosis II. Meiosis I separates homologous chromosomes into separate cells (1n, 2c), while meiosis II separates sister chromatids into gametes (1n, 1c). Meiosis due to aberrant cell division

Monosomy is a loss of 1 chromosome (pair becomes 1 chromosome):

• Turner syndrome Turner syndrome Turner syndrome is a genetic condition affecting women, in which 1 X chromosome is partly or completely missing. The classic result is the karyotype 45,XO with a female phenotype. Turner syndrome is associated with decreased sex hormone levels and is the most common cause of primary amenorrhea. Turner Syndrome is an example of monosomy:
  • Loss of 1 sex chromosome
  • Affected individuals present with a short and webbed neck, low-set ears, and short stature.
• Cri du chat syndrome is another example of monosomy:
  • Deletion of the short arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm of chromosome 5
  • Affected individuals present with laryngeal abnormalities.

Trisomy is a gain of 1 chromosome (pair becomes 3 chromosomes):

• Patau syndrome Patau syndrome Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13) (trisomy 13):
  • Caused by meiotic nondisjunction
  • Causes microcephaly, holoprosencephaly, polydactyly, and congenital heart defects
• Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down Syndrome (trisomy 21):
  • Caused by meiotic nondisjunction
  • Presents early in life as intellectual disability, physical growth delays, and characteristic facies (flat head, abnormal outer ears, slanted eyes)

Point Mutations

General

A point mutation is a mutation that affects only 1 nucleotide in a DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure sequence. The nucleotide change can lead to the following outcomes:

• Silent mutation
• Missense mutation
• Nonsense mutation

Silent mutation

• A change in the sequence of nucleotide bases that does not change the produced amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids
• Does not change the overall cellular function
• Silent mutations can lead to genetic diversity within a population and may be considered beneficial for a species.
• Silent mutations have been used in a research setting for vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination development and cloning.

Missense mutation

• Occurs when a change in a single base pair causes the substitution of a different amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids in the resulting protein
• May alter protein folding and affect protein function
• An example of a disease caused by a missense mutation is sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease:
  • Mutation within the beta chain of hemoglobin
  • 20th nucleotide has a GAG-to-GTG mutation.
  • Glutamic acid is replaced with valine.

Nonsense mutation

• A mutation in which a codon that corresponds to 1 of the 20 amino acids specified by the genetic code is changed to a chain-termination codon, resulting in truncation of the protein chain
• Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis:
  • Caused by a nonsense mutation of the CFTR gene
  • Results in thick mucus that leads to breathing difficulties and recurrent infections

Frameshift Mutations

• Results from nucleotide base insertion or deletion, changing the reading frame for the process of translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation
• The number of nucleotides inserted or deleted must not be divisible by 3, as the reading frame would not be altered and only 1 more or less nucleotide would be coded.
• Results in the alteration of all amino acids produced downstream from the mutation
• Errors that occur upstream lead to a more severe mutation.
• Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease is an example of a disorder caused by a frameshift mutation.

Expansion Mutations

• Also called trinucleotide repeat expansions
• Typically caused by slippage during DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication or DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair
• As a general rule, the larger the expansion, the more likely the expansion will cause a disease.
• Trinucleotide repeat expansion is the DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder.
• Examples of trinucleotide repeat expansions:
  • Huntington disease Huntington disease Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. It is caused by cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). The most common clinical presentation in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Huntington Disease:
    • Inherited neurodegenerative disease
    • Caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene
    • Typically, symptoms develop in the 4th–6th decades of life.
    • Physical capabilities degenerate and affected individuals develop dementia.
    • Larger expansions mean affected individuals have a more severe and earlier disease onset.
  • Fragile X syndrome Fragile X syndrome Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a genetic condition with X-linked inheritance. Both boys and girls may be affected, but the severity is much worse in boys. Characteristic features include a long face, prominent forehead and chin, large ears, flat feet, and large testes post-puberty for boys. Fragile X Syndrome:
    • Caused by cytosine-guanine-guanine (CGG) repeats
    • Classically presents with an elongated face and large, prominent ears
  • Friedreich ataxia:
    • Caused by guanine-adenine-adenine (GAA) repeats
    • Presents in late childhood with ataxia, neurological symptoms, and dysarthria

Clinical Relevance

• Huntington disease Huntington disease Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. It is caused by cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). The most common clinical presentation in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Huntington Disease: a neurodegenerative condition with an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inheritance. Affected individuals typically develop symptoms in their 30s, 40s, or 50s. The classic presentation is involuntary movements, psychiatric conditions, and intellectual problems. Huntington disease Huntington disease Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant mode of inheritance and poor prognosis. It is caused by cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene (HTT). The most common clinical presentation in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Huntington Disease is caused by trinucleotide repeat expansion of the CAG triplet in the huntingtin gene. There is no cure for this disorder and management is aimed at improving the quality of life.
• Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease: a neurodegenerative condition inherited in an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancefashion. Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease is caused by a mutation in hexosaminidase-A, leading to an accumulation of GM2 gangliosides. There is great variation in disease presentation and individuals may present anytime from early life into adulthood. The typical clinical features are motor weakness, cognitive changes, and hypersensitivity to stimuli. On physical examination, affected individuals are found to have a cherry-red spot on the macula. Management is supportive as there is no cure for this disease.
• Sickle cell disease: the most common genetic disease in the US. Sickle cell disease has an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinheritance. Sickle cell disease is caused by a mutation in the beta hemoglobin gene with valine replacing glutamic acid. Affected individuals may be asymptomatic or require frequent hospitalization for disease complications. Sickle cell disease complications include vaso-occlusive crises, acute chest syndrome, frequent infections, stroke, and pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism. While there is no cure, disease complications are treated and prevented as possible.