Single Gene Disorders

Question 1

What kind of proteins can be affected by mutations?

Answer 1

• -Enzymes
• -Transport and storage proteins
• -Structural proteins
• -Proteins involved in growth, differentiation and development
• -Receptor and signaling proteins

Question 2

Null mutation

Answer 2

Mutation that completely destroys a protein

Question 3

Loss-of-function mutation

Answer 3

Mutation reducing protein’s activity

Question 4

Gain-of-function mutation

Answer 4

Mutation altering protein’s activity or give it a new function (typically seen in signal transduction proteins)

Question 5

Mendelian modes of inheritance

Answer 5

1. Autosomal dominant
2. Autosomal recessive
3. X-linked dominant
4. X-linked recessive

Question 6

Recessive inheritance

Answer 6

Only present when there are two mutant alleles

Question 7

Typical proteins mutated in recessive inheritance disorders

Answer 7

Mostly observed in defects of enzymes and proteins involving transport and storage; can compensate for loss of one functional allele

Question 8

How are defective recessive alleles compensated for?

Answer 8

1. Protein working harder

2. More protein made

Question 9

Carrier of recessive genetic disease

Answer 9

Person with one normal dominant allele and one mutated recessive allele

Question 10

Compound heterozygote

Answer 10

Person affected by recessive disease with two mutant alleles that are not identical (contain different mutations)

Question 11

Dominant inheritance

Answer 11

Present when one mutant allele is sufficient to cause disease (occurs in heterozygote state)

Question 12

Typical proteins mutated in dominant inheritance disorders

Answer 12

Mostly observed in defects of structural proteins, proteins involved in growth/differentiation/development, and receptor/signaling proteins

Question 13

Causes of dominant inheritance (4)

Answer 13

1. Haploinsufficiency
2. Dominant negative effect
3. Gain-of-function mutation
4. Lack of backup (two-hit model)

Question 14

Haploinsufficiency

Answer 14

One functional allele isn’t enough – requires full gene dosage instead of half (ex. structural proteins that are produced in mass quantities)

Question 15

Dominant negative effect

Answer 15

Abnormal protein competing with wildtype form (ex. collagen; one wrong protein can disrupt whole structure)

Question 16

Lack of backup (two-hit model)

Answer 16

Predisposition to certain disorders (typically cancers) due to one mutation being inherited and the other spontaneously mutating

Question 17

Calculate expected genotype frequencies using Punnett square

Answer 17

Parents’ alleles are used as column and row headers with dominant alleles capitalized and recessive alleles in lowercase; possible allele combinations can be visualized
Dominant: affected (heterozygous) + healthy = 50% chance of heterozygous affected child
Recessive: carrier parents = 25% chance of affected child, 50% chance of carrier child

Question 18

Sex-determining region of Y

Answer 18

Where the genetic information for male development of embryo is found on Y chromosome

Question 19

Psuedoautosomal region of Y

Answer 19

Region that is homologous to X chromosome for proper alignment with X-chromosome in meiosis

Question 20

X-linked inheritance

Answer 20

Comes from a mutation on the X chromosome

Question 21

Autosomal inheritance

Answer 21

Comes from a mutation on an autosome

Question 22

Mitochondrial inheritance

Answer 22

Does not follow Mendelian rules of inheritance; inherited from mother; variable expression due to the many copies of mitochondrial DNA

Question 23

Pedigree

Answer 23

A chart to show whether a parent is a carrier of a disease and analyze familial patterns of a disease; can be used to make accurate estimate of risk for a person to be a carrier of a recessive disease and estimate the likelihood of a couple having an infected child

Question 24

Consanguineous mating

Answer 24

Mating between cousins (important in risk for recessive disorders)

Question 25

Lifetime risk for single gene disease

Answer 25

2%

Question 26

Genetic counseling

Answer 26

Counseling for parents seeking advice about the risk of having a child with a genetic disease; requires knowledge of parents’ genotypes and mode of inheritance of disease; performed by a certified genetic counselor

Question 27

X-chromosome inactivation

Answer 27

In the first week of development, cells inactivate one X-chromosome so that only the genes of the active X-chromosome are expressed; all progeny of the cells have same X-chromosome inactivated; X-chromosome mosaicism can occur if different X-chromosomes are silenced in different cells

Question 28

How do you conduct a simple linkage analysis?

Answer 28

A linkage/marker analysis is done by looking at certain set of genetic markers on a chromosome; the two genes present in the person with disease can be used to see which were the carrier genes from parents and if there are any other carriers in the family (look at example in notes)

Question 29

Recurrence risk

Answer 29

Possibility of next child having specific disease; normally remains the same no matter how many children since conceptions are statistically independent events

Question 30

Characteristics of autosomal recessive diseases

Answer 30

1. Affected children usually have unaffected parents 2. Both sexes are affected equally 3. Consanguinity increases risk

Question 31

What are examples of autosomal recessive diseases?

Answer 31

Phenylketonuria and cystic fibrosis

Question 32

Explain impact of consanguinity on risk for recessive disorders

Answer 32

Most people carry 2-3 recessive mutant alleles on average, and closely related individuals often carry those same recessive mutant alleles, which means that they are at higher risk for recessive genetic disorders; higher coefficient of inbreeding

Question 33

Coefficient of inbreeding

Answer 33

Describes degree of homozygosity - -Siblings share 50% of their genes, so a child between them would be homozygous for 25% of genes, making coefficient of inbreeding 25% for siblings - -Cousins have a coefficient of 1/16, meaning individual is homozygous in 1/16 of genes to other

Question 34

Inborn errors of metabolism (IEM)

Answer 34

Class of autosomal recessive disorders caused by defects in metabolic enzymes; each disease is rare but cumulative incidence is 1/300 births; many are screened for in newborn screens and can be acute or chronic

Question 35

Acute IEMs

Answer 35

Start in neonatal period and arise from defective metabolism of small molecules (amino acids, sugars, etc.); non-specific symptoms that often include lethargy, poor feeding, seizures, or characteristic smells

Question 36

Chronic IEMs

Answer 36

Arise from defects in storage and metabolism of large molecules (glycogen, proteoglycans, etc.)

Question 37

Phenylketonuria (PKU)

Answer 37

Prevalence: 1/2,900 (relatively rare) Mode of inheritance: AR, chronic IEM Pathology: defect on phenylalanine hydroxylase gene on chromosome 12 leading to difficulties in tyrosine metabolism Symptoms: musty odor, abnormal brain development Other: Newborn screening done (most prevalent IEM)

Question 38

Cystic fibrosis (CF)

Answer 38

Prevalence: 1/2000 (common) Mode of inheritance: AR Pathology: defect in gene for chloride channel on chromosome 7 (CFTR), often due to deletion of amino acid 508 in first nucleotide binding domain affecting post-translational processing Symptoms: thick mucus covering lung epithelium and GI tract Uses sweat chloride test, allele heterogeneity, modifier loci Treatment: maintaining lung function and aiding digestion

Question 39

Pancreatic sufficiency of CF

Answer 39

Pancreatic sufficient: patients with enough CFTR for normal digestion Pancreatic insufficient: patients that require supplementation with pancreatic enzymes

Question 40

Sweat chloride test

Answer 40

Measurement of the electric conductivity of the skin surface to test for cystic fibrosis (patients with CF have salty sweat with high electric conductivity)

Question 41

Allele heterogeneity

Answer 41

Harboring different mutations in the same gene, leading to different impact on function of gene product (reason for variation in pancreas function in CF patients)

Question 42

Modifier genes

Answer 42

Normal variations in activity of other proteins that can have an impact on the severity of other mutations (reason for variation in pancreas function in CF patients; known ones are MSD1, NBD1, NBD2)

Question 43

Fructose 1,6-bisphosphatase deficiency

Answer 43

Mode of inheritance: AR Pathology: fasting hypoglycemia See carbohydrate metabolism for more

Question 44

Sickle cell anemia

Answer 44

Mode of inheritance: AR Pathology: hemolysis See hemoglobinopathy for more

Question 45

Sucrase-isomaltase deficiency

Answer 45

Mode of inheritance: AR Pathology: sucrose/glucose polymer intolerane See carbohydrate metabolism for more

Question 46

Glycogen storage disorders

Answer 46

Mode of inheritance: AR Pathology: hypoglycemia, accumulation of glycogen See carbohydrate metabolism for more

Question 47

Characteristics of autosomal dominant diseases

Answer 47

1. Affected child has at least one affected parent 2. Both sexes affected equally 3. Can be transmitted from father to son 4. Often homozygotes more severely affected than heterozygotes

Question 48

Penetrance

Answer 48

Percentage of people with disease gene who develop symptoms; can be complete or incomplete Complete penetrance: if a patient has a certain disease, they will present with symptoms at some point Incomplete penetrance: patients with genotype for disease may not develop symptoms

Question 49

Expressivity

Answer 49

Severity of the symptoms; can be low, high, or variable | Variable expressivity: not all patients develop same set of symptoms (complicates risk analysis)

Question 50

Neurofibromatosis (NF)

Answer 50

Prevalence: 1/3500 (relatively rare) Mode of inheritance: AD Pathology: mutated neurofibromin (NF1) gene on chromosome 17 Symptoms: multiple tumors (including iris of eye called Lisch nodules and in CNS), café-au-lait spots, mental retardation Other: new mutations, variable expressivity

Question 51

Huntington Disease (HD)

Answer 51

Prevalence: 5/100,000 (very rare) Mode of inheritance: AD Pathology: Defect of huntingtin gene on chromosome 4 that causes CAG triplet expansions Symptoms: neurological disorders (ex. dementia, uncontrolled movement of limbs) Other: new mutations, triplet expansion, anticipation, gain-of-function

Question 52

Premutation

Answer 52

With Huntington Disease, a person with more than 40 repeats develops the disease; with 35-40 repeats they will most likely not develop it but the next generation will likely have it (= premutation)

Question 53

Anticipation

Answer 53

Severity of a disease increasing when transmitted through a pedigree due to escalating number of repeats; observed frequently in triplet expansion mutations such as HD

Question 54

Delayed age of onset

Answer 54

A disorder that does not manifest itself until later in life (ex. Huntington Disease does not display symptoms until about age 40)

Question 55

Achondroplasia

Answer 55

Mode of inheritance: AD Pathology: mutation in fibroblast growth factor receptor gene (FGFR3) on chromosome 4 Symptoms: small stature due to inhibition of bone growth Other: new mutations, reduced fitness (20% fertility), dominant negative allele, mutation hotspot

Question 56

Fitness

Answer 56

Chance of reproduction of an affected patient that will pass on the inherited disorder; many disorders reduce fitness by causing infertility or death before reproductive age; when fitness = 0, affected individual cannot reproduce at all

Question 57

Mutation hotspot

Answer 57

Chromosomal region where mutations occur frequently that normally consists of CG dinucleotide repeat that is methylated (ex. G1138 on FGFR3 gene in achondroplasia)

Question 58

What disorders often see new mutations? In which genes? Why?

Answer 58

Duchenne Muscular Dystrophy (dystrophin), Neurofibromatosis (NF1), Achondroplasia (FGFR3) --Genes are large, complex, or have mutation hotspots

Question 59

Ehlers-Danlos Syndrome (EDS)

Answer 59

Prevalence: 1/10000 for all collagen disorders Mode of inheritance: AR (mutations in enzymes required for processing) and AD (dominant negative due to misfolded collagen) Pathology: collagen disorder Other: genetic heterogeneity

Question 60

Osteogenesis imperfecta I (OI)

Answer 60

Mode of inheritance: AD Pathology: defective type I collagen Dominant negative alleles, allele heterogeneity

Question 61

Dominant negative effect of OI

Answer 61

2 Proα1 and one Proα2 chain assemble to form procollagen, and this is interrupted by a defective chain that disturbs the larger structure; cause of Type II (perinatal lethal), Type III (progressive deforming), and Type IV (mildest form)

Question 62

Haploinsufficiency of OI-1

Answer 62

One copy of the gene is not enough to satisfy demand for collagen molecules in tissue; cause of Type I (mild)

Question 63

Familial Hypercholesterolemia

Answer 63

Prevalence: 1/500 (frequent) Mode of inheritance: AD Pathology: defective LDL receptor; LDL levels are doubled in heterozygotes and quadrupled in homozygotes Other: allele heterogeneity

Question 64

Dominant inheritance of familial hypercholesterolemia

Answer 64

Any malfunction in the LDL receptor will cause elevated plasma LDL levels due to the fact that it is a transfer/storage protein and is required for the metabolism of cholesterol

Question 65

Gain-of-function mutations in RET gene

Answer 65

Can render signaling molecule constitutively active, causing Multiple Endocrine Neoplasia (MEN) due to proliferation of neuroendocrine cells; overrides action of wildtype product

Question 66

Loss-of-function mutations in RET gene

Answer 66

Can destroy the molecule’s ability to respond to stimulus, causing Hirschsprung disease due to impairment of colon neuron development; upsets development because of haploinsufficiency

Question 67

Barr bodies

Answer 67

Inactivated X-chromosomes that condense at the periphery of the nucleus; only found in females

Question 68

Characteristics of X-linked recessive disorders

Answer 68

1. No father-son transmission 2. Affected boys usually have unaffected parents 3. Males affected more frequently than girls 4. Seems to “skip generations”

Question 69

Duchenne Muscular Dystrophy (DMD)

Answer 69

Prevalence: 1/3000 (relatively rare) Mode of inheritance: XR Pathology: defect in dystrophin Other: new mutations, large target

Question 70

Glucose-6-phosphate dehydrogenase deficiency

Answer 70

Mode of inheritance: XR Pathology: sensitivity to H2O2-generating agents and fava beans See carbohydrate metabolism for more

Question 71

Characteristics of X-linked dominant disorders

Answer 71

1. No father-son transmission 2. All daughters of affected father are affected 3. Females more frequently affected 4. Typically lethal in males

Question 72

Leber’s Hereditary Optic Neuropathy (LHON)

Answer 72

Prevalence: 1/50000 (very rare) Mode of inheritance: mitochondrial Pathology: defect on mitochondrial DNA in ND1 gene Symptoms: deterioration of optic nerve, causing blindness early in adulthood Other: heteroplasmy

Question 73

Heteroplasmy

Answer 73

Cells contain varying fractions of defective mtDNA molecules in mitochondrial disorders

Question 74

Mode of inheritance explained by pedigree

Answer 74

Use chart from notes