[01.03a] Principles of Genetics & Overview of Genetic Pathology (Part 1) V2

Genetic Diseases and Types Genetic diseases

What type of diseases are far more common than generally realized?

50%

What percentage of spontaneous abortus have chromosomal abnormalities?

1%

What percentage of all newborns have gross chromosomal abnormalities?

5%

What percentage of individuals less than 25 years of age will have a serious disease with a genetic component?

Single Gene Disorders / Mendelian disorders

What type of genetic disorder involves a mutation in single genes with large effects and typically follows Mendelian inheritance patterns?

Chromosomal Disorders

What type of genetic disorder is caused by abnormalities at the chromosomal level?

Complex Multigenic Disorders

What type of genetic disorder was formerly referred to as multifactorial diseases and is influenced by both genetic and environmental factors?

Environmental factors

What specific factors may need to influence a complex multigenic disorder before the disease manifests?

Polymorphism

What term refers to variations of genes that are common in the population?

Multiple genes working hand in hand

In complex multigenic disorders, what produces certain phenotypes like height, eye color, or intelligence?

"Multifactorial diseases"

What are diseases called when several polymorphisms are present?

Mutations Permanent changes in the DNA

What are mutations defined as?

Germ cells and somatic cells

Where can mutations be seen?

Germ cells

If a mutation occurs in this type of cell, it can be passed down to progeny.

Somatic cells

If a mutation occurs in this type of cell, it cannot be passed down but is important in cancers and congenital malformations.

Blood

What type of sample is typically used for germline mutation testing?

Single Point Mutation / Substitution

What type of mutation involves a change in only one nucleotide in the DNA?

Missense or Nonsense

Single point mutations within coding sequences can be one of these two types.

Missense Mutation

What type of point mutation within a coding sequence may replace an amino acid?

Conservative missense mutation

What type of missense mutation causes little change to protein function?

Non-conservative missense mutation

What type of missense mutation leads to a biochemically different protein function?

Nonsense Mutation

What type of point mutation changes a codon to a "stop" codon?

UAG, UGA, UAA

What are the three stop codons mentioned in the context of nonsense mutations?

Truncated protein

What happens to a protein if a codon mutates into a stop codon?

Intron Mutation

What type of mutation can happen within noncoding sequences that may interfere with transcription factor binding?

Thalassemia

What genetic disorder is given as an example of an intron mutation interfering with transcription factor binding?

Multiples of three

If the base pairs involved in deletions and insertions are in this quantity, the reading frame remains intact.

Frameshift mutation

What type of mutation occurs if base pairs in deletion and insertion are not multiples of three?

Premature stop codon

What does a frameshift mutation usually form?

Cystic Fibrosis (CF)

What disease is an example of a three-base deletion that does NOT cause a frameshift mutation?

Trinucleotide-Repeat Mutation

What type of mutation is characterized by amplifications or repetitions of a sequence of three nucleotides?

Guanine (G) and Cytosine (C)

Which two nucleotides are usually involved in trinucleotide-repeat mutations?

Huntington’s Disease

What disease is an example of a trinucleotide-repeat mutation involving repeating CAG?

Fragile X syndrome

What disease is an example of a trinucleotide-repeat mutation involving repeating CGG?

Less than 50

According to Dr. Abesamis, what is the approximate number of trinucleotide repeats found in normal populations?

More than 200

At what approximate number of trinucleotide repeats do manifestations typically show?

Mitochondrial DNA (mtDNA) mutations

What type of mutation can only be passed through maternal inheritance?

Mothers to all offspring (male and female)

How do mothers transmit mtDNA?

Daughters

Which offspring of a mother can transmit mtDNA further to their progeny?

Genomic imprinting or gonadal mosaicism

What influences transmission when one of a person's parental chromosomes can be silenced, potentially leading to a problematic chromosome?

Definitions of Genetic Conditions Hereditary disorders

What term refers to disorders derived from one’s parents and transmitted in the germ line?

Congenital

What term describes a condition where the manifestation is already seen upon birth?

Not all genetic diseases are congenital

What is a key point regarding the relationship between genetic diseases and congenital conditions?

Huntington’s Disease

What is an example of a familial genetic disease that is not congenital, as its manifestation is delayed to adulthood?

Osteogenesis Imperfecta

What is an example of a congenital disorder where the problem gene was not necessarily inherited, but could be caused by a mutation during gametogenesis?

Recessive

What is the common expression pattern for many Mendelian disorders regarding phenotypic effects?

80-85%

What percentage of Mendelian disorders are familial in nature?

Partial (if heterozygous) or full (if homozygous)

How can the expression of Mendelian disorders be described?

Heterozygous expression

What type of expression is usually not as severe compared to a homozygous expression?

Sickle cell anemia (sickle cell trait)

What is an example of a heterozygous expression in which sickling only occurs under certain circumstances?

Codominance

What term means that both alleles of a gene pair contribute to the phenotype?

ABO blood groups

What is a classic example of codominance?

Pleiotropism

What term describes a single mutant gene having many effects?

p53 (in Li-Fraumeni syndrome)

What single mutant gene is an example of pleiotropism, leading to multiple cancers?

Genetic Heterogeneity

What term describes mutations at several loci producing the same trait?

Type 1 diabetes

What disease is an example of genetic heterogeneity, where multiple genes are found to contribute to the same effect?

Mendelian Transmission Patterns Autosomal Dominant

What inheritance pattern describes a condition where, in the heterozygous state, at least one parent is affected?

Both males and females

In autosomal dominant inheritance, which sexes are affected and can transmit the condition?

New mutations

What can explain cases where some autosomal dominant patients do not have affected parents?

Variations in penetrance and expressivity

What modifies the clinical features in autosomal dominant conditions?

Incomplete penetrance

What term describes a mutant gene being inherited but a normal phenotype being expressed?

Penetrance

What term refers to the proportion of those who inherit a gene and express its phenotype?

Variable expressivity

What term describes a trait seen in all individuals with the same mutated gene, but expressed differently?

Expressivity

What term refers to the variability in phenotypic expression among those who inherit a gene?

Adulthood

What is the typical onset for some autosomal dominant conditions, such as Huntington disease?

Enzymes

Autosomal dominant disorders are usually related to what type of proteins?

Loss-of-function

What is the most common autosomal dominant disease pattern?

Familial hypercholesterolemia

What disease is an example of a loss-of-function autosomal dominant disorder involving receptor defects?

Osteogenesis imperfecta

What disease is an example of a loss-of-function autosomal dominant disorder involving key structural proteins?

Gain-of-function

What autosomal dominant disease pattern involves an increase in a protein’s normal function or a new activity unrelated to its normal function?

Both sexes are affected and generations are not skipped

What are the key characteristics of an autosomal dominant pedigree?

50%

In a Punnett Square for an autosomal dominant condition, if 'N' is the disease gene, what percentage of offspring will manifest the disease?

Autosomal Recessive Inheritance Autosomal Recessive (AR)

What is the largest category of Mendelian disorders?

Both alleles

In autosomal recessive inheritance, how many alleles need to be mutated for a manifestation to occur?

Carrier-state

If only one allele is present in autosomal recessive inheritance, what is the individual considered?

Parents of the affected individual

In autosomal recessive inheritance, what group of people does the trait usually not affect?

1 in 4 chance (25%)

What is the chance of siblings having an autosomal recessive trait?

Consanguineous marriage

If a mutant gene occurs with a low frequency, an affected individual is most likely a product of what type of marriage?

Uniform expression of defect, complete penetrance, and early onset

What are three features of autosomal recessive diseases regarding their manifestation?

New mutations

What are rarely detected clinically in autosomal recessive disorders?

Enzymes

What type of proteins do mutated genes typically encode in autosomal recessive disorders?

Almost all inborn errors of metabolism

What category of diseases is included in autosomal recessive disorders, with some being part of newborn screenings?

Both sexes can be affected, generations can be skipped

What are the key characteristics of an autosomal recessive pedigree?

Both parents are at least heterozygous for the gene

What condition must be met for autosomal recessive disorders to be possible in offspring?

25% affected homozygous, 50% normal but carrier, 25% normal

If both parents are heterozygous for an autosomal recessive gene, what are the expected percentages of offspring genotypes/phenotypes?

X-Linked Disorders X-linked

What term describes all sex-linked disorders?

Recessive

Most X-linked disorders follow what inheritance pattern?

Infertility

What does Y-linked inheritance usually cause?

Males

Which sex usually manifests X-linked recessive diseases due to being hemizygous for X-linked mutant genes?

Females

Which sex tends to be carriers for X-linked recessive diseases?

Vitamin D-resistant rickets and Alport syndrome

What are two examples of X-linked dominant conditions?

Affected heterozygous female

Who transmits X-linked dominant conditions to 50% of sons and 50% of daughters?

Sons

An affected male with an X-linked disorder will not transmit the disease to which of his offspring?

Random inactivation of normal genes in the X-chromosome

What can lead to partial expression in heterozygous females with X-linked conditions?

Glucose-6-phosphate dehydrogenase deficiency

What X-linked recessive disorder is principally expressed in males, with females being carriers susceptible to drug-induced hemolytic reactions?

All daughters affected, males normal

What is the outcome if an affected male (X-linked dominant) and a normal female have offspring?

50% of daughters affected, 50% of sons affected

What is the outcome if an affected heterozygous female (X-linked dominant) and a normal male have offspring?

X-linked recessive

Which X-linked inheritance pattern is more common?

All sons normal, all daughters are normal but carrier

What is the outcome if a normal female and an affected male (X-linked recessive) have offspring?

50% of sons affected, 50% of daughters are carriers

What is the outcome if a carrier female and a normal male (X-linked recessive) have offspring?