19 Single Gene Disorders Flashcards
What is pseudoautosomal regions
some homologous regions on X and Y chromosome
What is Polymorphism and make an example and where is this gene located
When a specific site on a chromosome has multiple alleles in the population
β-globin gene, chromosome 11p15
Name different type of mutations
Missense mutations Nonsense mutations Insertion Deletion In-frame Frameshift loss-of-function Gain-of-function
Example for missense mutation
what is substituted in it
sickle cell disease is caused by a missense mutation
substitution of valine for glutamic acid in the β-globin
Examples for loss-of-function mutations
Phenylketunuria
Tay-Sachs
Sickle cell disease
CF
Examples for Gain-of-function mutations
Oncogens
What is a proband
The first affected individual to be identified in the family in a pedigree
Name some Autosomal Dominant inheritance
Familial hypercholesterolemia (LDL receptor deficiency) Huntington disease Neurofibromatosis type 1 Marfan syndrome Acute intermittent porphyria
what is the clue for AD inheritance in a pedigree
typically observed in multiple generations of a pedigree
Name some Autosomal Recessive inheritance
Sickle cell anemia
Cystic fibrosis
Phenylketonuria
Tay-Sachs disease (hexosaminidase A deficiency)
what is the clue for AR inheritance in a pedigree
Autosomal recessive diseases are typically seen in only one generation of a pedigree
Consanguinity
Name some X-linked Recessive Inheritance
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)
What does hemizygous mean
males are said to be hemizygous for the X chromosome in X-linked Recessive Inheritance
what is the clue for X-linked recessive inheritance in a pedigree
much more commonly in males
Skipped generations are commonly seen
Male-to-male transmission is not seen
What is the Mechanisms of X inactivation
Occurs in the blastocyst (-100 cells)
Gene called XIST is responsible
Methylation of gene regions
produce heterochromatin and Barr body
What are Characteristics of x-inactivation
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
how much protein does sexual chromosomes code
why does x inactivated
Y carries only about 30 protein-coding genes
X carries hundreds of protein-coding genes
equalize the amount of protein encoded by X
Name some X-linked Dominant Inheritance
Hypophosphatemic Rickets
Fragile X Syndrome
Symptoms and penetrance of Fragile X Syndrome
Males: 100% penetrance • Mental retardation • Large ears • Prominent jaw • Macro-orchidism (usually postpubertal) Females: 60% penetrance • Mental retardation
What is penetrance
Percentage of individuals who are known to have the disease-causing genotype who display the disease phenotype
Name some Mitochondrial Inheritance
Leber hereditary optic neuropathy
MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
Myoclonic epilepsy with ragged red muscle fibers
What is Heteroplasmy
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
What is Variable Expression
Disease severity varies from patient to patient but they all manifest the symptoms
What are some examples of Variable Expression
Hemochromatosis
Neurofibromatosis Type 1
xeroderma pigmentosum
hemophilia
what factors are affecting Variable Expression and what are their examples
Environmental Influences: bleeding in Hemochromatosis or UV exposure in xeroderma pigmentosum
Allelic Heterogeneity: missense vs nonsense in hemophilia - variety between families
Heteroplasmy
Modifier Loci
inheritance, penetrance, symptoms, gene of hemochromatosis
autosomal recessive, penetrance of 15%
arthritis, significant hepatomegaly, diabetes, and “bronze” skin, cirrhosis
mutation C282y
incomplete penetrance and also an example of variable expression
What is Incomplete penetrance
no presentation or phenotype vs decreased symptoms in variable expression
What are some examples of Incomplete penetrance
Retinoblastoma
Inherited Breast Cancer
hemochromatosis
Explain pattern of Inheritance, penetrance and mechanism of gene expression in Rb
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%
Explain pattern of Inheritance, penetrance in Inherited Breast Cancer
BRCA I & BRCA II
AD follow two hit theory
70% penetrance
What is Pleiotropy
single disease-causing mutation affects multiple organ systems
What are some examples of Pleiotropy
Marfan syndrome
Cystic fibrosis
What is etiology and symptoms of Marfan
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)
What is Locus Heterogeneity
same disease phenotype can be caused by mutations in different loci
What are some examples of Locus Heterogeneity
Osteogenesis Imperfecta Type 2
What is Etiology, chromosome defect and pattern of inheritance in Osteogenesis Imperfecta Type 2
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
What are some examples of Delayed Age of onset
Acute intermittent porphyria (peri- or postpubertal), Huntington disease
Hemochromatosis
Familial breast cancer
What is pattern of inheritance, symptoms, chromosome defect, kind of gene(also in normal people) involvement in Huntington
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
What is Anticipation
recent generation of a pedigree develop a disease at an earlier age or with greater severity
What is the etiology of Anticipation
gradual expansion of trinucleotide repeat polymorphisms within or near a coding gen
What are some examples of Anticipation
Huntington disease
Fragile X syndrome
Myotonic dystrophy
Friedreich ataxia
What is pattern of inheritance, symptoms, kind of gene involvement in Fragile X syndrome
X dominant
Mental retardation, Large ears and jaw
Post-pubertal macro-orchidism (males)
Attention deficit disorder (in females)
CGG 5’UTR
What is pattern of inheritance, symptoms, kind of gene involvement in Myotonic dystrophy
Autosomal dominant
Muscle loss, Cardiac arrhythmia, Testicular atrophy
Frontal baldness, Cataracts
CTG 3’UTR
What is pattern of inheritance, symptoms, name and kind of gene involvement in Friedreich ataxia
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
What is Imprinting
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
What are some examples of Imprinting
Prader-Willi Syndrome
Angelman Syndrome
What are Symptoms, chromosome and gene involved in Prader-Willi Syndrome
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
What are Symptoms, chromosome and gene involved in Angelman Syndrome
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
