Exam 2: Genetic Disorders

Autosome

Any of the 22 pairs of non-sex chromosomes.

Sex chromosomes

The chromosome pair responsible for sex determination.

Gene

An inherited DNA-encoded factor that helps determine a characteristic.

Allele

One of two or more versions of a gene located at the same locus.

Locus

The specific place on a chromosome occupied by an allele.

Gene = inherited instruction; allele = version; locus = location.

How do gene, allele, and locus differ?

Wild-type allele

The most common allele in a population.

Variant allele

A permanent variation from the wild-type allele that may be benign or disease-causing.

Mutation

A permanent change in the DNA sequence.

A variant is not automatically disease-causing.

What important distinction should be made about genetic variants?

Genotype

The set of alleles possessed by an individual.

Phenotype

The observable characteristics or traits of an organism.

Genotype = alleles; phenotype = observable traits.

★ HIGH YIELD — Contrast genotype and phenotype.

Characteristic/character

An attribute or feature possessed by an organism.

Heterozygote

An individual with two different alleles at a locus.

Homozygote

An individual with two identical alleles at a locus.

One allele is inherited from each parent.

What is the basic Mendelian origin of an allele pair?

F1 generation

First filial generation after crossing the parental generation.

F2 generation

Second filial generation.

3:1 dominant:recessive phenotype ratio

What phenotype ratio did Mendel observe in the F2 generation?

Capital letter = dominant allele; lowercase letter = recessive allele

How are dominant and recessive alleles conventionally represented?

Dominant trait

A trait requiring only one copy of the allele for expression.

Recessive trait

A trait requiring two copies of the allele for expression.

Genetic disease

A disease caused by abnormal expression/function of one or more genes producing a clinical phenotype.

Chromosomal, mitochondrial, monogenic, and multifactorial/polygenic defects

What broad causes of genetic disease are listed?

Hereditary disease

A disease caused by defective genes inherited from parents.

Somatic mutation

A mutation arising in a body cell.

Germ-cell mutation

A mutation occurring in cells that can contribute to gametes and be inherited.

Somatic = stays with the individual; germline = can pass to future generations.

★ HIGH YIELD — Contrast somatic and germ-cell mutations.

Gene variants can suppress transcription, alter mRNA, alter protein function, or interfere with protein synthesis.

What major levels of gene expression can variants disrupt?

Loss-of-function mutation

A variant that produces reduced or nonfunctional protein activity.

Gain-of-function mutation

A variant that produces excessive or abnormal protein activity.

Single-nucleotide variant / point mutation

Substitution of a single DNA base.

Missense mutation

★ HIGH YIELD — Which point mutation substitutes one amino acid for another?

Conservative missense

Amino-acid substitution to one with similar chemical properties.

Nonconservative missense

Amino-acid substitution to one with very different chemical properties.

Nonsense mutation

A point mutation that creates a stop codon and truncated protein.

Silent mutation

A base substitution that still encodes the same amino acid.

Promoter/enhancer mutation

A noncoding variant that can alter transcription.

Splice-site mutation

A noncoding variant that can disrupt posttranscriptional splicing.

Noncoding mutations can still alter gene expression or mRNA processing.

Why can mutations outside coding regions still cause disease?

Punnett square

A visual representation used to predict possible inheritance outcomes.

Aa × Aa → 1/4 AA : 1/2 Aa : 1/4 aa

★ HIGH YIELD — What is the genotype ratio from two heterozygous parents?

Aa × aa → 1/2 Aa : 1/2 aa

What genotype ratio results from a heterozygote crossed with a homozygous recessive individual?

AA × aa → all Aa

What offspring result from homozygous dominant × homozygous recessive?

Pedigree analysis

The study of human inheritance using phenotypic data across generations.

Square = male; circle = female; filled = affected

What are the basic pedigree symbols for sex and affected status?

Vertical transmission

Phenotype seen generation after generation.

Horizontal transmission

Phenotype clustered among siblings but absent in earlier generations.

Vertical suggests dominant; horizontal/skipping suggests recessive.

★ HIGH YIELD — What quick pedigree clue distinguishes dominant from recessive patterns?

Sex ratio

What pedigree feature asks whether males and females are affected equally?

Segregation

What pedigree feature asks which parent transmits the trait to which offspring?

Father-to-son transmission rules out X-linked inheritance.

★ HIGH YIELD — What does father-to-son transmission immediately tell you?

Autosomal dominant

An inheritance pattern affecting both sexes about equally and usually appearing every generation.

Affected heterozygote × unaffected → about 50% affected

★ HIGH YIELD — What is the typical recurrence risk in an autosomal-dominant Aa × aa cross?

Affected offspring usually have an affected parent.

What parental pattern supports autosomal dominant inheritance?

Unaffected individuals do not transmit the dominant trait in the classic pattern.

What does an unaffected individual imply in autosomal dominant inheritance?

Autosomal recessive

An inheritance pattern affecting both sexes about equally and tending to skip generations.

Two unaffected carrier parents can have affected offspring.

★ HIGH YIELD — What parental pattern strongly suggests autosomal recessive inheritance?

Aa × Aa → 25% affected, 50% carriers, 25% unaffected noncarriers

★ HIGH YIELD — What are the expected outcomes of two autosomal-recessive carriers?

Consanguinity

What family-history feature increases the likelihood of autosomal recessive disease?

X-linked dominant

An X-linked trait that generally does not skip generations and often affects more females.

Affected father → all daughters affected, no sons affected

★ HIGH YIELD — What father-offspring pattern identifies X-linked dominant inheritance?

Heterozygous affected mother → ~50% sons and ~50% daughters affected

What offspring pattern occurs from a heterozygous X-linked-dominant mother?

X-linked recessive

An inheritance pattern that usually affects more males and may skip generations.

Carrier mother → about half of sons affected

★ HIGH YIELD — What is the classic maternal transmission pattern for X-linked recessive disease?

No father-to-son transmission

★ HIGH YIELD — Can an X-linked trait be directly transmitted from father to son?

Affected father + normal mother → all daughters carriers, no affected sons

★ HIGH YIELD — What happens to offspring of an X-linked-recessive affected father and wild-type mother?

0%

★ HIGH YIELD — What percentage of sons receive an X-linked recessive allele directly from an affected father?

Y-linked / holandric

An inheritance pattern occurring only in males.

Affected father → all sons

★ HIGH YIELD — What transmission pattern identifies Y-linked inheritance?

Y-linked traits do not skip generations in the classic pattern.

What generational pattern is expected for Y-linked traits?

Mitochondrial inheritance

Cytoplasmic inheritance of mitochondrial DNA through the mother.

Affected mother → all children inherit; affected father → no children inherit

★ HIGH YIELD — What pedigree pattern identifies mitochondrial inheritance?

Maternal inheritance

From which parent is mitochondrial DNA inherited?

Homoplasmy

A mitochondrial state in which the mtDNA population is essentially the same type.

Heteroplasmy

A mixture of normal and mutant mtDNA.

Heteroplasmy can produce variable disease severity among offspring.

★ HIGH YIELD — Why can maternally related individuals have different mitochondrial disease severity?

Mitochondrial genetic bottleneck

Random partitioning can create oocytes with different proportions of mutant and normal mtDNA.

Incomplete dominance

Heterozygous phenotype is intermediate between the two homozygous phenotypes.

Codominance

Both alleles are simultaneously expressed in the heterozygous phenotype.

Incomplete dominance = intermediate/blended; codominance = both expressed.

★ HIGH YIELD — Contrast incomplete dominance and codominance.

Tay-Sachs disease

Which human example does the slide list under incomplete dominance?

AB blood type and sickle cell anemia

Which examples are listed under codominance?

Amelogenesis imperfecta (AI)

A genetic disorder of tooth development affecting enamel.

Small, discolored, pitted/grooved teeth with rapid wear and breakage

What general dental abnormalities can occur in AI?

Primary and permanent teeth

Which dentitions can be affected by amelogenesis imperfecta?

4 types and 17 subtypes

How many AI types/subtypes does the lecture mention overall?

AI may occur alone or as part of a multisystem syndrome.

What are the two general clinical contexts in which AI can occur?

Hypoplastic AI

★ HIGH YIELD — Which AI type is characterized by a deficiency in the amount of enamel?

Defect in enamel matrix formation

What is the underlying enamel-development defect in hypoplastic AI?

Reduced tooth size, thin enamel, small spaces, yellow-brown discoloration

What clinical features characterize hypoplastic AI?

Hypomineralized / hypocalcified AI

Which AI type is caused by defective enamel mineralization?

The enamel may be normal thickness but is porous, rough, weak, and easily worn.

★ HIGH YIELD — How does hypomineralized enamel differ from hypoplastic enamel?

Creamy white, yellow, or brown with a chalky texture

What appearance is associated with hypomineralized/hypocalcified AI?

Hypomature / hypomaturation AI

Which AI type results from defective enamel maturation?

Failure to properly remove enamel-matrix proteins and promote hardening

★ HIGH YIELD — What process fails in hypomaturation AI?

Enamel is present but pathologically soft and may appear whitish.

What characterizes the enamel in hypomaturation AI?

Hypoplastic = quantity problem; hypomineralized = mineral quality problem; hypomature = matrix-removal/hardening problem

★ HIGH YIELD — Distinguish the three major AI clinical types.

AMELX, ENAM, MMP20, and FAM83H

Which four genes are emphasized in amelogenesis imperfecta?