BIOCHEMISTRY- Genetics Flashcards
It´s when both alleles contribute to the phenotype of the heterozygote
Codominance
Give two examples of Codominance
Blood groups A, B, AB a1 antitrypsin deficiency
What is Variable expressivity?
When the phenotype varies among individuals with same genotype
2 patients with neurofibromatosis type 1 may have varying disease severity… its an example of?
Variable expressivity
Not all the individuals with a mutant genotype show the mutant phenotype
Incomplete prentrance
An example of incomplete penetrance…
BRCA1 gene mutations do not always result in breast or ovarian cancer
What is a pleiotropy?
One gene contributes to multiple phenotypic effects
Increase severity or earlier onset of disease in succeeding generations
Anticipation
This disease its an example of Anticipation
Trinucleotide repeat disease (Huntington disease)
Retinoblastoma and the Two-Hit hypothesis its an example of?
Loss of Heterozygosity
What is a loss of heterozygosity?
If a patient inherits or develops a mutation in a tumor supressor gene, the complementary allele must be deleted/mutated before cancer develops
What is a Dominant negative mutation?
Exerts a dominant effect. A heterozygote produces a nonfuctional altered protein that also prevents the normal gene product from functioning
Its the tendency for certain alleles at 2 linked loci to occur together more often than expected by chance
Linkage disequilibrium
What is a Mosaicism?
Presence of genetically distinct cell lines in the same individual. Arises from mitotic errors after fertilization
This kind of mosaicism mutation propagates through multiple tissue or organs
Somatic Mosaicism
What is a Gonadal Mosaicism?
Mutation only in egg or sperm cells
What is worst if the McCune-Albright syndrome is a somatic mutation or if it´s mosaicism?
If it´s somatic is lethal, but survivable if mosaic
Mutations at different loci can produce a similar phenotype
Locus heterogeneity
Which disease it´s an example of Locus heterogeneity?
Albinism
Diferent mutations in the same Locus produce the same phenotype
Allelic heterogeneity
This disease is an example of diferent mutations in the same Locus produce the same phenotype
B- thalassemia
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease
Heteroplasmy
Offspring receives 2 copies of a chromosome from 1 parent and no copies from other parent
Uniparental disomy
What does a Heterodisomy (heterozygous) indicates?
Meiosis I error
Indicates a Meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair
Isodysomy (homozygous)
Is the uniparental disomy an euploid or an aneuploid?
Euploid
When do we consider an Uniparental disomy?
In an individual manifesting a recessive disorder when only one parent is a carrier
What does the Hardy-Weinberg law assumptions include?
No mutations ocurring at the locus Natural selection is not occurring Completely random mating No net migration
What happens or what is affected in the imprinting?
At some loci, only one allele is active, the other is inactive
What is the factor that causes the imprinting?
By methylation
If there is one allele inactivated, what will happen?
Deletion of the active allele that will end up in disease
What´s wrong in Prader Willi and Angelman syndromes?
Imprinting, Mutation or deletion of genes on chromosome 15
In Prader Willi syndrome, who suffers the imprinting?
Maternal imprinting
Gene from mom is normally silent and paternal gene is deleted/ mutated
Prader Willi syndrome
How many cases of Prader Willi syndrome are uniparental disomy?
25% of cases
What does it mean uniparental disomy in Prader Willi sindrome?
Two maternally imprinted genes are received; no parental gene received
What kind of findings do we see in Prader Willi?
hyperphagia
obesity
intellectual disability
hypogonadism
hypotonia
This syndrome is related to a parental imprinting…
Angelman syndrome
Two paternally imprinted genes are received, no maternal gene received… How many percentage of cases of this syndrome do wee see?
It´s an paternal uniparental dismony of Angel syndrome which corresponds to the 5 % percentage of the cases
Characterized for inappropriate laughter (“happy puppet”), seizures, ataxia, and severe intellectual disability
Angelman syndrome
What is the explanation of Angelman syndrome?
Gene from dad is normally silent and maternal gene is deleted/mutated
Which are the modes of inheritance?
Autosomal dominant
Autosomal recessive
X-linked recessive
X-linked dominant
Mitochondrial inheritance
What is this pattern of inheritance?
Autosomal Dominant
Which are the characteristics of the autosomal dominant pattern of inheritance?
Often pleiotropic
Family history crucial to diagnosis.
25% of offspring from 2 carrier parents are affected. Often due to enzyme deficiencies. Usually seen in only 1 generation
Autosomal recessive
Between an autosomal Dominant and autosomal recessive inheritance, which one is more commonly severe?
Autosomal recessive inheritance
When is more common for the autosomal recessive to present?
Patients often present in childhood
Which kind of patients have increased risk to have this mode of inheritance?
Consaguineous families
Who is affected in this mode of inheritance? and which percentage?
It is a X-linked recessive inheritance. Sons of heterozygous mothers have a 50% chance of being affected
Is it posible to have a male to male transmission on the X-linked recessive inheritance?
No male to male transmision
Is it posible to see a female affected by this mode of inheritance ?
Yes, but it has to be homozygous to be affected
In which disease do we see this mode of inheritance ?
This is a X-linked dominant inheritance. The Hypophosphatemic rickets follows this pattern of inheritance.
Who transmits the disease in the X-linked dominant inheritance?
Transmitted through both parents
If the mother is the carrier of X-linked dominant Hypophosphatemic rickets, Who can be affected?
Mother transmit to 50% of daughters and sons
Inherited disorder resulting in increase phosphate wasting at proximal tubule
Hypophosphatemic rickets
Who transmits this mode of inheritance? A clue is that all offspring of affected females may show signs of disease
Mitochondrial inheritance. Transmitted only through the mother
What is the explanation that there is a variable expression in a population or even within a family in mitochondrial inheritance?
Heteroplasmy
This inherite disease is characterized by myopathy, lactic acidosis and CNS disease. In the muscle biopsy often shows ragged red fibers
Mitochondrial myopathies
Name examples of Autosomal dominant diseases
Autosomal domiant polycystic kidney disease
Familial adenomatous polyposis
Familial hypercholesterolemia
Hereditary Hemorrhagic telangiectasia
Hereditary spherocytosis
Huntington disease
Marfan syndrome
Multiple endocrine neoplasias (MEN)
Neurofibromatosis type 1 and 2
Tuberous sclerosis
von Hippel-Lindau disease
This autosomal dominant disease manifest always bilateral, massive enlargement of kidneys due to multiple large cysts
Autosomal domiant polycystic kidney disease
Which genes are mutated in Autosomal polycystic disease?
85% of cases PKD 1
15% of cases PKD 2
Which chromosomes are affected in PKD 1 and 2?
For PKD 1 is chromosome 16 and for PKD 2 is chromosome 4
In this autosomal dominant disease there is a mutation on chromosome 5 (APC gene)
Familial adenomatous polyposis
For the familial adenomatous polyposis when does the colon becomes covered with adenomatous polyps?
After the puberty
What is the common evolution of Familial adenomatous polyposis?
Progresses to colon cancer unless colon is resected
This is an inherited autosomal dominant disorder of blood vessels
Hereditary hemorragic Telangiectasia
What other name does Hereditary Hemorragic Telangiectasia has?
Osler Weber Rendu
Which are the common findings in Hereditary Hemorragic Telangiectasia?
Arteriovenous malformations (AVMs), GI bleeding, hematuria, telangiectasia, reccurent epistaxis, skin decolorations
Which kind of inheritance mode does the Hereditary spherocytosis follows?
Autosomal Dominant inheritance
Where is the defect in the Hereditary spherocytosis?
Spheroid erythrocytes due to spectrin or ankyrin defect
Which laboratory findings do we see in the hereditary spherocytosis?
Hemolytic anemia
Increase MCHC
This is the ideal treatment for hereditary spherocytosis
Splenectomy
Which chromosome is affected in Huntington disease?
chromosome 4
Which neurotransmitter levels are decreased in the brain in Huntington disease?
GABA and ACh
What are the common findings in Huntington disease?
depression
progressive dementia
choreiform movements
caudate atrophy
What is affected in Huntington disease?
Trinucloetide repeat disorder CAG
On what depends the age of onset in Huntington disease?
The more CAG repeats the younger the age of onset
What mode of inheritance is Huntington disease releated?
Autosomal Dominant disease
The main affectance in this autosomal dominant disease is the conective tissue
Marfan syndrome
Where is the gene mutation in Marfan syndrome?
Fibrilin 1 gene
Which are the main three organs affected by Marfan syndrome?
Skeleton, Heart and Eyes
What skeletal findings are common in Marfan syndrome patients?
Tall with long extremities, pectus excavatum, hypermobile joints and long tappering fingers and toes (arachnodactyly)
When a patient with Marfan syndrome has cystic medial necrosis aorta, which could be te complication?
Aortic incompetence and dissecting aortic aneurysms; floppy mitral valve
This are the eye manifestations in Marfan syndrome
Subluxation of lenses, typically upward and temporally
This autosomal dominant disease is related with ret gene asociated with MEN 2A and MEN 2B
Multiple endocrine disease
Neurocutaneous disorder characterized by cafe au lait spots and cutaneous neurofibromas
Neurofibromatosis type 1
What other name does Neurofibromatosis type receives?
Von Recklinghausen disease
Which are the genetic characteristics of Neurofibromatosis type 1?
Autosomal dominant
100% penetrance
Variable expression
Which gene and chromosome are mutated on von Recklinghausen disease?
NF1 gene on chromosome 17
This autosomal dominant disease has the mutation on NF2 gene chromosome 22
Neurofibromatosis type 2
Which are the findings in Neurofibromatosis type 2
Bilateral acoustic shwannomas, juvenile cataracts, meningiomas, and ependymomas
Neurocutaneous disorder with multiple organ system involvement, characterized by numerous hamartomas
Tuberous sclerosis
Is the Tuberous sclerosis an autosomal dominant or autosomal recessive disease?
Autosomal dominant disease
How is the penetrance and expression in Tuberous sclerosis?
Incomplete penetrance and variable expression
This disease is affected in chromosome 3 (3p), disorder characterized by development of numerous tumors
von Hippel-Lindau disease
With which gene deletion is associated von Hippel Lindau disease?
VHL gene
The Tumor associated with von Hippel Lindau, are they benign or malignant?
Both, benign and malignant
Which mode of inheritance does cystic fibrosis belongs?
Autosomal recessive disease
This are examples of autosomal recessive disease
Albinism, ARPKD (formerly known as infantile polycystic kidney disease), cystic fibrosis, glycogen storage disease, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except Hunter syndrome), phenylketonuria, sickle cell anemia, sphinolipidoses (except Fabry disease), thalassemias, Wilson disease
Which is the mos common lethal genetic disease in caucasian population?
Cystic fibrosis
Genetically, where is the site of affection in cystic fibrosis?
defect in CFTR gene on chromosome 7
Commonly where is the site of deletion in cystic fibrosis?
Phe508
What kind of channels does the CFTR encodes?
ATP-gated CL- channel
What is the function of the ATP-gated CL- channel?
secrets Cl- in lungs and GI tract, and reabsorbs Cl- in sweet glands
After the mutation in CFTR, what happens next?
It leads to misfolded protein→protein retained inRER and not transported to cell membrane, causing decrese Cl- (and H20) secretion
So… after the increase intracellular Cl-, who else is going to be affected?
Results in compensatory increase Na+ reabsorption via epithelial Na+ channels, which leads to increase H20 reabsorption
So… if there is an increase of intracellulary Cl-, which leads to increase Na+ reabsorption via epithelial, with increase watter reabsoption… Anatomically which are going to be the results?
Abnormally thick mucus secreted into Lungs and GI tract
What else does the Na+ reabsorption is going to cause?
More negative transepithelial potential difference
Which is the diagnostic tool for Cystic fibrosis?
Elevated Cl- concentration in sweat
Which levels of Cl- do we consider diagnostic?
> 60 mEq/L
This are other findings for Cystic Fibrosis
Alkalosis and hypokalemia
How is possible the Alkalosis and Hypokalemia in the cystic fibrosis patient?
Because of extracellular H2O/Na+ losses and concomitant renal K+/H+ wasting
Which medicines analogues the extracellular effects in Cystic fibrosis?
Loop diuretic
This are the complication that can be seen?
Recurrent pulonary infections (Pseudomonas), chronic bronchitis and bronchiectasis, pancreatic insufficiency, malabsorption and stetorrhea nasal polyps.
In newborns, which are the findings in Cystic Fibrosis?
Meconium ileus
Which vitamins are affected by Cystic fibrosis?
Fat solible vitamin (A,D, E, K)
Inthe reproduction aspect, what elses does the cystic fibrosis can have?
Infertility in males (absence of vas deferens, absent sperm)
This are the main treatments for cystic fibrosis
N-acetylcysteine and dornase alfa
What purpose does it has the treatment with N-acetylcysteine
loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins)
Name X-linked recessive disorders
G6PD deficiencym, Lesch Nyhan syndrome, Duchenne (and Becker) muscular distrophy, Hemophilia A and B, Ocular albinism, Fabry disease, Brutton afamaglobulinemia, Wiskott Aldrich, Hunter syndrome, Ornithine transcarbamylase deficiency
On what depends the affectance in female carriers of X-linked recessive disorders?
Female carriers can be variably affected depending on the percentage inactivation of the X chromosome carrying the mutant vs normal gene
What kind of genetic disorder is the Duchenne dystrophie?
X-linked frameshift mutation
Which protein is truncated in Duchenne syndrome?
Dystrophin protein
What happens to the muscle if there is a deleted dystrophin?
Accelerated muscle breakedown
How is the progression of Duchenne dysthropie?
Weakness begins in pelvic girdle muscles and progress superiorly
Why do we see a pseudohypertrophy of calf muscles in Duchenne dystrophie?
Due to fibrofatty replacement of muscle
What manuever or sign is common in Duchenne patients?
Gower maneuver
What is about the Gower maneuver, in Duchenne dystrophie?
Patients use upper extremity o help them stand up
At what age is the onset of Duchenne dystrophie?
before 5 years old
This is the common cause of death in Duchenne distrophies
Dilated cardiomyopathy
Which gene has the longest coding region?
Dystrophin gene (DMD gene)
Which is the importance of dystrophin?
It connects the intracellular cytoskeleton (actin) to the transmembrane proteins α and β dystroglycan, which are connected to the axtracellular matrix
What happens to the muscle if there is a lack of dystrophin?
Results in myonecrosis
Which laboratory are you specting to see altered in Duchenne distrophie?
Increase CPK and aldolase
What confirms the diagnosis of Duchenne distrophie?
Western blot and muscle biopsy
What is the diference genetically speaking between Becker and Duchenne dysthropies?
Usually Becker is a X linked point mutation in dystrophin gene (NO FRAMESHIFT)
Which dystrophie is more severe Duchenne or Becker?
Duchenne is more severe
Which is the age of onset in Becker dystrophie?
In adolescence or early adulthood
True or False… a deletion can cause both Duchenne and Becker dystrophie
True
This kind of dystrophie is due to CTG trinucleotife repaet expansion in the DMPK gene
Myotonic type 1
If there is a CTG trinucleotide repeat expansion in the DMPK gene, What will happen?
Abnormal expression of myotonin protein kinase
A myotonic type 1 patient what clinical findings are present?
myotonia, muscle wasting, frontal balding, catarcts, testicular atrophy and arrhytmia
Name 3 types of muscular dystrophies
Duchenne, Becker and Myotonic type 1
This autism patient is brough by his mother… What clinical findings do you see… What do you suspect?
Long face with large jaw, large everted ears+ austism suspect Fragile X syndrome in this patient
This syndrome is consider the 2nd most common cause of genetic intellectual disability (after Down syndrome)
Fragile X syndrome
Genetically, What is affected in Fragile X syndrome patients?
X-linked defect affecting the methylation and expression of the FMR1 gene
Which are the findings in Fragile X syndrome patients?
postpubertal macroochidism (enlarged testes), long face with large jaw, large everted ears, autism, mitral valve prolapse
This is another genetical finding in X fragile syndrome
Trinucleotide repeat CGG
This four diseases are examples of trinucleotide repeat expansion
Huntington disease
Myotonic dystrophy
Friedreich ataxia
Fragile X syndrome
This nucleotide CGG is reapeted in which disease?
fragile X syndrome
Which nucleotides are repeated in Freiedreich ataxia?
GAA
What is the name of this trinucleotide CTG repeat expansion disease?
Myotonic dystrophy
This nucleotide are repeated in Huntington disease
CAG
This three diseases are example of trisomies
Down syndrome
Edwards syndrome
Patau syndrome
Which is the prevelance of trisomy 21?
1:700
This are the main findings in Down syndrome
Intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirschprung disease, congenital heart disease, Brushfield spots
Which kind of congenital heart disease are most commonly found in trisomy 21?
Ostium primum type atrial septal defect
When Down syndrome patients are >35 years old, what kind of diseases are at higher risk of?
ALL, AML, and Alzheimer disease
Genetically, Which is the cause of trisomy 21?
95% of cases due to meiotic nondisjunction of homologous chromosomes
Which factor plays an important role on having meiotic nondisjunction of homlogous chromosomes in Down syndrome patient?
Advanced maternal age; from 1:1500 in women <20 to 1:25 in women > 45 years old
The other 5% of cases of Down syndrome are due to…
4% of cases due to Robertsonian translocation
1% of cases due to mosaicism
Why the mosaicism can happen in Down syndrome patients?
No maternal association; post fertilization mitotic error
Which kind of findings are shown during the First trimester ultrasound? and Which laboratory findings?
Increase nuchal translucency and hypoplastic nasal bone; serum PAPP-A is decrease and free β-hCG is increase
What does the quad screen study during pregnancy?
α fetoprotein
β-hCG
Estriol
Inhibin A
What does the quad screen shows during the Second trimester in Down syndrome?
decrease α fetoprotein, increase β-hCG, decrease estriol, increase inhibin A
Severe intellectual disability, rocker bottom feet, micrognatia (small jaw), low set ears, clenched hands, prominent occiput, congenital heart disease… Which chromosome is affected? Which syndrome are we speaking of?
Chromosome 18, Edwards syndrome
Which kind of genetic disorder is Edwards syndrome?
Autosomal Trisomy
It´s the prevalence of trisomy 18
1:8000
Which is the prognosis of Edwards syndrome?
Death usually occurs within 1 year of birth
Most common trisomy resulting in live birth after Down syndrome
Edwards syndrome
How is the PAPP-A and free β-hCG in Edwards syndrome at the first trimester?
Both are decrease
What does the quad screen shows in Edwards syndrome?
decrease α fetoprotein, decrease β hCG, decrease estriol and decrease or normal inhibin A
Which chromosome is affected in Patau Syndrome?
Trisomy 13
Which is the prevalence of Patau syndrome?
1:15,000
This are the findings in Patau syndrome
Severe intellectual disability, rocker bottom feet, microphthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease
It is the prognosis of trisomy 18
Death usually occurs within 1 year of birth
What does the screen during the first trimester of pregnancy shows in Patau syndrome?
decrease β hCG, decrease PAPP-A and increase nuchal translucency
What is the problem in the first image and with the second image?
Nondisjunction in meiosis I in the first one
Nondisjunction in meiosis II in the second one
When does a Rebertsonian translocation occurs?
Nonreciprocal chromosomal translocation. Occurs when the long arms of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost
What is an acrocentric chromosome?
chromosome with centromeres near their ends
Which is one of the most common type of translocation?
Robertsonian translocation
Which chromosome pairs does the Robertsonian translocation most commonly involves?
Chromosome pairs 13, 14, 15, 21 and 22
What could happen if there is an unbalanced translocation?
Can result in miscarriage, stillbirth and chromosomal imbalance
What do you suspect with this case?
Cri-du-chat syndrome
Which trisomies are examples of Robertsonian unbalanced translocation?
Down syndrome and Patau syndrome
Congenital microdeletion of short arm of chromosme 5
Cri-du-chat syndrome
Which are the findings in Cri-du-chat syndrome?
High-pitched crying/mewing, microcephaly, moderate to severe intellectual disability, ephicanthal folds, cardiac abnormalities
What does Cri du chat means?
Cri du chat= Cry of the cat
This patient has a microdeletion of long arm of chromosome 7… which syndrome are thinking?
Williams syndrome
What else does the microdeletion of chromosome 7 includes?
Deleted region includes elastin gene
Which are the findings in Williams syndrome?
Distinctive elfin fascies, intellectual disability, hypercalcemia, well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems
Why can the hypercalcemia be present in Williams syndrome?
Because of an increase sensitivity ti vitamin D
Genetically, where is the problem in DiGeorge syndrome and the Velocardiofacial syndrome?
22q11 deletion
Which are the variable presentations of 22q 11 deletion?
Cleft palate
Abnormal facies
Thymic aplasia
Cardiac Defects
Hypocalcemia
What are the consecuences of a Thymic aplasia?
T cell deficiency
Which is the explanation of the hypocalcemia in 22q11 deletion?
Secondary to parathyroid aplasia
Which are the characteristics of DiGeorge syndrome?
Thymic, parathyroid and cardiac defects
It´s a microdeletion of 22q11 represented by palate, facial, and cardiac defects
Velocardiofacial syndrome
Where is the aberrant development of the DiGeoede syndrome?
3rd and 4th branchial pouches
