19 Single Gene Disorders

Question 1

What is pseudoautosomal regions

Answer 1

some homologous regions on X and Y chromosome

Question 2

What is Polymorphism and make an example and where is this gene located

Answer 2

When a specific site on a chromosome has multiple alleles in the population
β-globin gene, chromosome 11p15

Question 3

Name different type of mutations

Answer 3

Missense mutations
Nonsense mutations
Insertion
Deletion
In-frame
Frameshift
loss-of-function
Gain-of-function

Question 4

Example for missense mutation

what is substituted in it

Answer 4

sickle cell disease is caused by a missense mutation

substitution of valine for glutamic acid in the β-globin

Question 5

Examples for loss-of-function mutations

Answer 5

Phenylketunuria
Tay-Sachs
Sickle cell disease
CF

Question 6

Examples for Gain-of-function mutations

Answer 6

Oncogens

Question 7

What is a proband

Answer 7

The first affected individual to be identified in the family in a pedigree

Question 8

Name some Autosomal Dominant inheritance

Answer 8

Familial hypercholesterolemia (LDL receptor deficiency)
Huntington disease
Neurofibromatosis type 1
Marfan syndrome
Acute intermittent porphyria

Question 9

what is the clue for AD inheritance in a pedigree

Answer 9

typically observed in multiple generations of a pedigree

Question 10

Name some Autosomal Recessive inheritance

Answer 10

Sickle cell anemia
Cystic fibrosis
Phenylketonuria
Tay-Sachs disease (hexosaminidase A deficiency)

Question 11

what is the clue for AR inheritance in a pedigree

Answer 11

Autosomal recessive diseases are typically seen in only one generation of a pedigree
Consanguinity

Question 12

Name some X-linked Recessive Inheritance

Answer 12

Duchenne muscular dystrophy
Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase [HGPRT] deficiency)
Glucose-6-phosphate dehydrogenase deficiency
Hemophilia A and B
Red-Green colour blindness
Menke’s Disease
Ornithine transcarbamoylase (OTC) deficiency
SCID (IL-receptor γ-chain deficiency)

Question 13

What does hemizygous mean

Answer 13

males are said to be hemizygous for the X chromosome in X-linked Recessive Inheritance

Question 14

what is the clue for X-linked recessive inheritance in a pedigree

Answer 14

much more commonly in males
Skipped generations are commonly seen
Male-to-male transmission is not seen

Question 15

What is the Mechanisms of X inactivation

Answer 15

Occurs in the blastocyst (-100 cells)
Gene called XIST is responsible
Methylation of gene regions
produce heterochromatin and Barr body

Question 16

What are Characteristics of x-inactivation

Answer 16

Random: 50% of active is paternal, 50% is maternal
Fixed: once occurs stays throughout life
Incomplete: tips of both the long and short arms, that are not inactivated
One remain from any number of X

Question 17

how much protein does sexual chromosomes code

why does x inactivated

Answer 17

Y carries only about 30 protein-coding genes
X carries hundreds of protein-coding genes
equalize the amount of protein encoded by X

Question 18

Name some X-linked Dominant Inheritance

Answer 18

Hypophosphatemic Rickets

Fragile X Syndrome

Question 19

Symptoms and penetrance of Fragile X Syndrome

Answer 19

Males: 100% penetrance
• Mental retardation
• Large ears
• Prominent jaw
• Macro-orchidism (usually postpubertal)
Females: 60% penetrance
• Mental retardation

Question 20

What is penetrance

Answer 20

Percentage of individuals who are known to have the disease-causing genotype who display the disease phenotype

Question 21

Name some Mitochondrial Inheritance

Answer 21

Leber hereditary optic neuropathy

MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Myoclonic epilepsy with ragged red muscle fibers

Question 22

What is Heteroplasmy

Answer 22

Sometimes a specific mutation is seen in only some of the mitochondria

Variations in heteroplasmy can result in substantial variation in the severity of expression

Question 23

What is Variable Expression

Answer 23

Disease severity varies from patient to patient but they all manifest the symptoms

Question 24

What are some examples of Variable Expression

Answer 24

Hemochromatosis
Neurofibromatosis Type 1
xeroderma pigmentosum
hemophilia

Question 25

what factors are affecting Variable Expression and what are their examples

Answer 25

Environmental Influences: bleeding in Hemochromatosis or UV exposure in xeroderma pigmentosum Allelic Heterogeneity: missense vs nonsense in hemophilia - variety between families Heteroplasmy Modifier Loci

Question 26

inheritance, penetrance, symptoms, gene of hemochromatosis

Answer 26

autosomal recessive, penetrance of 15% arthritis, significant hepatomegaly, diabetes, and "bronze" skin, cirrhosis mutation C282y incomplete penetrance and also an example of variable expression

Question 27

What is Incomplete penetrance

Answer 27

no presentation or phenotype vs decreased symptoms in variable expression

Question 28

What are some examples of Incomplete penetrance

Answer 28

Retinoblastoma Inherited Breast Cancer hemochromatosis

Question 29

Explain pattern of Inheritance, penetrance and mechanism of gene expression in Rb

Answer 29

Autosomal dominant loss-of-function mutation Both Rb gene must be mutated: "loss of heterozygosity" will make the disease appear: Two hit theory Penetrance of 90%

Question 30

Explain pattern of Inheritance, penetrance in Inherited Breast Cancer

Answer 30

BRCA I & BRCA II AD follow two hit theory 70% penetrance

Question 31

What is Pleiotropy

Answer 31

single disease-causing mutation affects multiple organ systems

Question 32

What are some examples of Pleiotropy

Answer 32

Marfan syndrome | Cystic fibrosis

Question 33

What is etiology and symptoms of Marfan

Answer 33

``` A mutation in the gene that encodes fibrillin skeletal abnormalities (thin, elongated limbs, pectus excavatum, pectus carinatum), hypermobile joints ocular abnormalities (frequent myopia and detached lens) cardiovascular disease (mitral valve prolapse and aortic aneurysm) ```

Question 34

What is Locus Heterogeneity

Answer 34

same disease phenotype can be caused by mutations in different loci

Question 35

What are some examples of Locus Heterogeneity

Answer 35

Osteogenesis Imperfecta Type 2

Question 36

What is Etiology, chromosome defect and pattern of inheritance in Osteogenesis Imperfecta Type 2

Answer 36

AD, Defect in type 1 collagen 100% of individuals are the result of a new mutation in the family Two memberson chromosome 17, third is on chromosome 7

Question 37

What are some examples of Delayed Age of onset

Answer 37

Acute intermittent porphyria (peri- or postpubertal), Huntington disease Hemochromatosis Familial breast cancer

Question 38

What is pattern of inheritance, symptoms, chromosome defect, kind of gene(also in normal people) involvement in Huntington

Answer 38

Autosomal dominant progressive dementia, loss of motor control, and affective disorder, Death 10-15 years after onset Gain-of-function mutation on chromosome 4 Normal huntingin genes have fewer than 27 CAG repeats in the 5' coding region premutations of 27-35 repeats are seen: can be inherited by generally by males more than 39 repeats develop symptoms

Question 39

What is Anticipation

Answer 39

recent generation of a pedigree develop a disease at an earlier age or with greater severity

Question 40

What is the etiology of Anticipation

Answer 40

gradual expansion of trinucleotide repeat polymorphisms within or near a coding gen

Question 41

What are some examples of Anticipation

Answer 41

Huntington disease Fragile X syndrome Myotonic dystrophy Friedreich ataxia

Question 42

What is pattern of inheritance, symptoms, kind of gene involvement in Fragile X syndrome

Answer 42

X dominant Mental retardation, Large ears and jaw Post-pubertal macro-orchidism (males) Attention deficit disorder (in females) CGG 5'UTR

Question 43

What is pattern of inheritance, symptoms, kind of gene involvement in Myotonic dystrophy

Answer 43

Autosomal dominant Muscle loss, Cardiac arrhythmia, Testicular atrophy Frontal baldness, Cataracts CTG 3'UTR

Question 44

What is pattern of inheritance, symptoms, name and kind of gene involvement in Friedreich ataxia

Answer 44

Autosomal recessive Early onset progressive gait and limb ataxia, Areflexia in all 4 limbs, Hypertrophic cardiomyopathy Axonal sensory neuropathy, Kyphoscoliosis GAA Intron 1 in frataxin gene Life expectancy about 40

Question 45

What is Imprinting

Answer 45

small number of genes are transcriptionally active only when transmitted by one of the two sexes Occurs during gametogenesis During gametogenesis in the offspring, is erased and re-established according to the sex of the individual Involves methylation and other mechanisms

Question 46

What are some examples of Imprinting

Answer 46

Prader-Willi Syndrome | Angelman Syndrome

Question 47

What are Symptoms, chromosome and gene involved in Prader-Willi Syndrome

Answer 47

Neonatal hypotonia, Poor feeding in neonatal period, Behavior problems (temper tantrums), Moderate mental and developmental retardation, Hypogonadism, underdeveloped genitalia Hyperphagia (overeating) and obesity by ages 2-4 years, Small hands and feet Deletion from paternal 15q11-13 that include SNRPN , Very low recurrence risk

Question 48

What are Symptoms, chromosome and gene involved in Angelman Syndrome

Answer 48

Severe mental retardation, Seizures, Ataxia, Puppet-like posture of limbs, Happy disposition: Happy Puppet syndrome Deletion from maternal 15q11-13 include a ubiquitin pathway known as UBE3A, Very low recurrence risk