Exam Two

Down Syndrome

caused by having a whole extra or extra parts of chromosomes 21

25% survive until birth

features include open mouth and protruding tongue from low oral muscle tone, flat nasal bridge, low set ears, and upslanting eyes

intellectual disability may be varied

increased risk for leukemia and heart disease

Trisomy 21 Down Syndrome

having three copies of chromosomes 21

results from meiotic nondisjunction

most common (95% of cases)

Robertsonian Translocation Down Syndrome

21q fuses with 14q or 22q, trisomy only for 21q arm

related to family history

seen in 4% of cases

Translocation Down Syndrome

21q-21q, p arms degrade and q arms converge

rare

Partial 21q Down Syndrome

trisomy for specific genes on the 21q arm of chromosome

specific genes can be narrowed down in patients

rare

Diagnosis of Down Syndrome

cells taken from amniotic fluid (invasive) or from mom’s plasma (noninvasive)

can also be checked before implantation in IVF

karyotyping, microarray, sequence genome

Microdeletion & Duplication Syndromes

the addition or subtraction of contiguous segments or genes from aberrant recombination

can cause developmental delays, intellectual disabilities, and dysmorphic features

DiGeorge Syndrome

30 genes deleted in 22q11.2 from unequal recombination

haploinsufficient region

TBX1 deleted causing heart defects

Cri Du Chat Syndrome

autosomal deletion in 5p

cat cry

idiopathic

mostly sporadic (90% de novo/after fertilization)

Idiopathic

disease of unknown cause

Imprinting Disorders & Microdeletions

one parent’s allele is methylated and not expressed

if the expressed allele is deleted, it causes sickness

Imprinting

gene from one parent is methylated and off

monoallelic

Prader-Willi Syndrome

deletion of 15q paternal section

causes intellectual disability and obesity from overeating and an inability to sense fullness

Angelman Syndrome

deletion of maternal 15q segment

affects the nervous system

Sex Determination

if SRY is present, testis and male-specific features develop

primal gonads are ambipotent and the default pathway is ovaries

Puberty

development of secondary sex phenotypes that involve autosomes

Y Chromosome

has less than 100 genes that make 24 proteins mostly for male features

includes the SRY gene

had two psuedoautosomal regions for recombination with X chromosome

X Inactivation Center (XIC)

Xq13.2

XIST gene makes ncRNA expressed from future randomly inactivated X

Aneuploidy of Sex Chromosomes

less severe than autosomal aneuploidy because extra Xs are inactivated and Ys have few genes

Klinefelter Syndrome

XXY male

caused by nondisjunction from either parent

decrease in male hormones leading to low muscle and bone density, low libido, and low facial hair

infertile and have no germ cells (usually how they get diagnosed)

Turner Syndrome

X_ female

has side effects because 15% of genes active on inactivated X are not there

XY with Female Features

decreased SRY function due to SRY mutation, DAX1 duplication that suppresses SRY, SOX9 mutation that is a target for SRY, or NR5A1 mutation that does not turn on SOX9

XX with Male Features

identified as male at birth then diagnosed at puberty with small testes and breasts

results from SRY translocation to X chromosome, SOX3 duplication similar to SRY, or SOX9 duplication target of SRY

Disorders of Neurodevelopment

affects cognition, communication, behavior, and/or motor skills

can involve overlapping diagnoses

results from genomic imbalance of 100s-1,000s of genes

Fragile X Syndrome

X-linked intellectual disability

most common form of moderate intellectual diability and considered on the autism spectrum

results from FMR1 mutation on X chromosome with CGG repeats in promoter causing the cell to methylated and silence it because it looks like a CpG island

Genotype

alleles

genetic makeup

Phenotype

observed trait

physical attributes

Discrete Phenotype

a trait that has a clear difference

sick or not sick

Continuous Phenotype

traits occur on a continuum with a range of measurements

Homozygous Genotype

having two of the same alleles

Heterozygous Genotype

having two different alleles

Compound Heterozygous Genotype

having two different mutant alleles

Hemizygous

having only one of a gene

Single-Gene Disorder

disorder caused by one gene or locus

classical Mendelian inheritance patterns

proportions are fixed and predictable

Pleiotropic

one gene has many phenotypes and can affect many different organs at different point of life

due to genes being expressed in many different tissues and expressed at different points in life

Penetrance

probability of getting disease

regardless of severity

Expressivity

severity of disease/expression

same genotype but different phenotype/severity

Pedigree

family tree/pattern of transmission

Proband

subject of interest in a pedigree

Sibs

siblings (brothers, sisters) in a pedigree

Kindred

extended family in a pedigree

1st Degree Relatives

parents, siblings, and offspring in a pedigree

2nd Degree Relatives

grandparents, grandchildren, aunts, uncles, nephews, and nieces in a pedigree

3rd Degree Relatives

first cousins in a pedigree

Consanguineous

common ancestor/inbreeding

Sporadic Case

new mutation in proband

no family history and did not inherit

Mitochondrial Genes Inheritance Pattern

100% maternal inheritance

cytoplasm is 99.9% from mother and 0.1% from father and egg destroys father’s cytoplasm

mitochondria have 37 genes that make 13 proteins and their own ribosomes

mutations affect many tissues, especially high metabolism tissues

Recessive Mutation

sick if both copies are mutated or you only have one copy that happens to be mutated

Dominant Mutation

having one mutated copy makes you sick

Codominant

both alleles expressed

A Blood Type

from I^A allele

has A antigens and B antibodies

B Blood Type

from I^B allele

had B antigen and A antibodies

AB Blood Type

has I^A and I^B alleles

has A and B antigen and no antibodies

universal acceptor

O Blood Type

from two i alleles

has no additional antigens and both A and B antibodies

universal donor

Hemophilia A

recessive X-linked disease resulting from a single gene mutation

mutation in factor VIII which regulates blood clotting, causing more blood clotting in affected

also called “royal disease” because it was common in royal families where there was more inbreeding

Dominant X-Linked Mutation with Male Lethality

embryonic death and sick males are not observed

females live and are sick

Rett Syndrome

results from an X-linked dominant mutation with male lethality

MECP2 gene mutated

neurodevelopmental disorder

Dominant X-Linked Mutation with Male Sparring

males are sparred and are carriers but are not affected

heterozygous females are affected

X-Linked Epilepsy

dominant X-linked mutation with male sparring

protocadherin 19 mutation that causes mosaic neurons in heterozygous females and communication between neurons in disrupted

males have a similar gene on the Y chromosome that compensates

Incomplete Dominance

two alleles combine to create a new phenotype

heterozygous looks different from homozygous variants

Pseudoautosomal Inheritance

in males, X and Y can recombine in pseudoautosomal regions

can have male to male transmission if X_a transferred to Y

SHOX mutation is an example

Mosaic

one zygote with more than one cell lineage

mutation after fertilization

Segmental Mosaicism

patch of mutated cells

Germline Mosaicism

parent’s somatic cells are normal but mutation is in the gametes

all offspring are sick

Dynamic Mutations

result from more than or equal to three repeating tandem nucleotides

changes in different generations

mainly affects neurological disorders

wild-type is considered a certain number of repeats

Huntington’s Disease (HD)

degeneration of brain tissues from CAG repeats that code for glutamine and make proteins sticky and they clump together

results from incomplete dominant dynamic mutation

having more repeats at birth makes it more likely someone will get the disease, and repeats continue to accumulate throughout life

Mitochondrial Segregation

mitochondria randomly go to each cell during cell division

mtDNA is also randomly distributed during mitochondrial division

allows for variable phenotypes in cells

Heteroplasmy

having both wild-type and mutant mitochondria

Homoplasmy

having only wild-type or only mutant mitochondria

Mitochondria/Cytoplasm Transfer

therapy for woman with mitochondrial disease who wants children

cytoplasm taken out of egg and donor cytoplasm with healthy mitochondria added

need 80% healthy mitochondria

Nuclear Transplant

therapy for woman with mitochondria disease who wants children

nucleus injected into donor egg without a nucleus but with healthy mitochondria

2% mutant mitochondria contaminates

Multiple Alleles

one gene can have more than two alleles/mutations that can affect the severity and pleiotropy

cystic fibrosis is one of these with 1,000s of possible alleles

Clinical Heterogeneity

different mutations in the same gene leads to different phenotypes

for example LMNA mutations can cause six different diseases

Locus Heterogeneity

mutations in different genes cause the same disease because they are involved in the same pathway

for example retinitis pigmentosa can be caused by 44 autosomal mutation and 2 X-linked mutations

Multifactorial Diseases

health conditions caused by multiple genes and environmental factors

Familial Aggregation

when a trait, behavior, or disorder occurs more frequently in a family than in the general population, indicating a possible genetic contribution

Relative Risk Ratio for Familial Aggregation

prevalence of disease in relatives/prevalence of disease in general population

=1 means no familial aggregation

>1 means increased familial aggregation

Case-Control Study for Familial Aggregation

compares the patient and their relatives against a control

control should be about the same age and ethnicity as patient

Concordant

when two people (especially twins) share a trait or characteristic

Discordant

when two people (especially twins) do not share the same trait or characteristic

Ascertainment Bias

a systematic distortion in the collection of data that can lead to inaccurate results

more research attention

Recall Bias

patients do not accurately remember a past event or experience

Modifier Genes

genes that affect the expression of other genes

Digenic Inheritance

pattern on inheritance where two genes must both have pathogenic variants for a disease to occur

retinitis pigmentosa is an example

Population Genetics

genetic variation within populations

Hardy-Weinberg Equilibrium

conserved observed allelic frequency to expected genotypic frequency

requires no mutation, random mating, no gene flow, large population size, and no natural selection

can be used to predict the future risk of disease

(A + a)² = 1

A² + 2Aa + a² = 1

Observed Allelic Frequency

the proportion of a specific allele found within a population, calculated by directly counting the occurrences of that allele in a sample and dividing by the total number of alleles at that gene locus in a sample

one letter

Expected Genotypic Frequency

the predicted proportion of individuals in a population that will have a specific genotype, calculated based on the allele frequencies in the population

two letters

CCR5

white blood cell surface receptor and coreceptor for HIV

mutated allele for this gene has a frameshift mutations resulting in a nonfunctional protein from a premature stop (HIV resistance)

Nonrandom Mating

mating within subgroups and not randomly

Hardy-Weinberg cannot be used

Cultural and Religious Mating

a type of nonrandom mating where you mate within cultural and/or religious groups

decreases genetic diversity

Assortative Mating

a type of nonrandom mating where you mate with people with similar traits (deafness, blindness, dwarfism)

decreases genetic diversity

Consanguineous Mating

a type of nonrandom mating where you mate with others in the same family

decreases genetic diversity

Rh

an antigen on the red blood cell

Rh^-

recessive allele with no antigen

common in white Americans (1 in 6)

Hemolytic Disease of the Newborn

if a fetus is Rh⁺ and fetal blood enters the blood of a Rh^- mother, she makes antibodies for Rh

these antibodies will attack the next fetus if it is Rh⁺

injection of antibodies can be used to destroy Rh⁺ blood cells and prevent this (RhoGAM)

Heterozygous Advantage

being heterozygous is better than being homozygous dominant or homozygous recessive

sickle cell is an example