MCQ 3 Flashcards
What causes Deletion Syndromes?
- usually an error in crossover in meiosis
- unbalanced exchange of genes
- one chromosome with duplication; other with deletion
What type of chrome disorder presents with Turner Syndrome?
Sex chromosome aneuploidy disorder. Patient has an abnormal number of sex chromosomes
Describe pt population of Turner syndrome?
Female with missing X chromosome (XO)
How is Turner Syndrome diagnosed?
Karyotype Test
What causes Turner Syndrome?
Caused by sperm lacking X chromosome
Describe mosaic Turner syndrome
- Often milder
- some cells have 45 X, but other cells have 46 XX
What causes mosaic Turner Syndrome?
Mitotic nondisjunction during post-zygotic cell division
20% of pts w/ Miller-Dieker Syndrome inherit the _______ from a parent who carries__________
deletion / a balanced chromosomal rearrangement
Describe the etiology of Miller-Dieker Syndrome
contiguous gene deletion syndrome caused by heterozygous deletion of 17p13.3
mechanism responsible for microdeletions
recombination at segmental duplication
normal couple has recurrent spontaneous miscarriages. what is the most common cause? What testing will confirm?
balanced translocation / standard karyotyping
What is the most likely cause of partial deletion and partial duplication involving the same chromosome?
parental chromosomal abnormalities most likely caused pericentric inversion
Where does the Robertsonian translocation usually occur?
between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22)
-Onset at neonatal to adulthood
-Progressive pulmonary disease
-Exocrine pancreatic insufficiency
-Obstructive azoospermia
-Elevated sweat chloride
concentration
-Growth failure
-Meconium ileus
Cystic Fibrosis
Mutation of cystic fibrosis?
CFTR Mutation
Sickle cell disease pathogenesis
-Hemoglobin is composed of four subunits, two α subunits encoded by HBA on chromosome 16 and two β subunits encoded by the HBB gene on chromosome 11 -The Glu6val mutation in β-globin decreases the solubility of deoxygenated hemoglobin and causes it to form a gelatinous network of stiff fibrous polymers that distort the red blood cell, giving it a sickle shape Glutamate to valine mutation causing sickled RBCs
Sickle cell disease phenotype
- Onset at childhood
- Anemia
- Infarction
- Asplenia
Sickle Cell
Disease inheritance
autosomal recessive
Beta-globin
Glu6Val
Mutation
Sickle Cell
Disease
Turner syndrome pathogenesis
Without a second X chromosome, oocytes in fetuses and neonates with TS degenerate, and their ovaries atrophy into streaks of fibrous tissue. Oocytes can develop but cannot be maintained
Turner
Syndrome phenotype
- Prenatal onset
- Short stature
- Ovarian dysgenesis
- Sexual immaturity
Female
Monosomy X
Turner
Syndrome
Sex
Development
Disorder (46,
XX Male) pathogenesis
-SRY is a DNA-binding protein that alters chromatin structure by bending DNA altering gene expression -SRY is necessary for the formation of male genitalia and the absence forms female genitalia SRY in females causing male genitalia
Sex
Development
Disorder (46,
XX Male) phenotype
-Prenatal onset
-Sterility
-Reduced secondary sexual features
-Unambiguous genitalia mismatched
to chromosomal sex
Sex
Development
Disorder (46,
XX Male)
y-linked or chromosomal
SRY
Translocation
Sex
Development
Disorder (46,
XX Male)
Absence of
paternally derived
15q11-
q13
Prader-Willi
Syndrome
Prader-Willi
Syndrome inheritance
Chromosomal deletion, uniparental
disomy
Prader-Willi
Syndrome phenotype
- Onset at infancy
- Infantile feeding difficulties
- Childhood hyperphagia and obesity
- Hypotonia
- Cognitive impairment
- Short stature
- Dysmorphism
Prader-Willi
Syndrome pathology
-Deletion of 15q11-q13 during male meiosis gives rise to children with PWS because children formed from a sperm carrying the deletion will be missing genes that are active only on the paternally derived 15q11-q13. -The mechanism underlying this recurrent deletion is illegitimate recombination between low-copy repeat sequences flanking the
Miller-Dieker
Syndrome pathology
More than 50 genes have been mapped within the MDS deletion region in 17p13.3, but only the LIS1 gene (MIM 601545) has been associated with a specific phenotypic feature of MDS; heterozygosity for a LIS1 mutation causes lissencephaly MDS deletion and LIS1 mutation
Miller-Dieker
Syndrome phenotype
- Prenatal onset
- Lissencephaly type 1 or type 2
- Facial dysmorphism
- Severe global intellectual disability
- Seizures
- Early death
17p13.3
Heterozygous
Deletion
Miller-Dieker
Syndrome
autism pathology
-16p11.2 microdeletion is one of many microdeletion/ microduplications that recur due to low-copy repeat sequences (LCRs) with high sequence homology flanking the deleted or duplicated DNA Microdeletions causing developmental/intellectual disability
Autism phenotype
-Onset at birth or first 6 months of life -Intellectual disability to normal intelligence -Impaired social and communication skills or frank autism spectrum disorder -Minor dysmorphic features
Autism inheritance
autosomal dominant or de novo
16p11.2
Deletion
Syndrome
Autism
Xeroderma
Pigmentosum pathogenesis
-Caused by mutations affecting the global genome repair subpathway of nucleotide excision repair or by mutations affecting postreplication repair -Loss of caretaker function required for maintenance of genome integrity causing oncogenic mutations Cancer risk from error with nucleotide excision repair
Xeroderma
Pigmentosum phenotype
- Onset at childhood
- UV light sensitivity
- Skin cancer
- Neurological dysfunction
Xeroderma
Pigmentosum Inheritance
autosomal recessive
Xeroderma
Pigmentosum phenotype
- Onset at childhood
- UV light sensitivity
- Skin cancer
- Neurological dysfunction
Defect of
Nucleotide
Excision Repair
Xeroderma
Pigmentosum
Thrombophilia pathogenesis
-The coagulation system maintains a delicate
balance of clot formation and inhibition;
however, venous thrombi arise if coagulation
overwhelms the anticoagulant and fibrinolytic
systems
-Impaired Factor V function to accelerate the
conversion of prothrombin to thrombin
-PROC mutation impairing Protein C function
(inactivates Factor V)
Coagulation impaired by errors with
Factor V and PROC function with Protein
C
Thrombophilia phenotype
- Onset at adulthood
- Deep venous thrombosis
Thrombophilia inheritance
autosomal dominant
FV and PROC
Mutations
Thrombophilia
Retinoblastoma pathogenesis
-The retinoblastoma protein (Rb) is a tumor
suppressor that plays an important role in regulating the progression of proliferating
cells through the cell cycle and the exit of
differentiating cells from the cell cycle.
-Retinoblastoma-associated RB1 mutations
occur throughout the coding region and
promoter of the gene
Issue with tumor repressor
Retinoblastoma phenotype
- Onset at childhood
- Leukocoria
- Strabismus
- Visual deterioration
- Conjunctivitis
Retinoblastoma inheritance
autosomal dominant
RB1 Mutation
Retinoblastoma
Neurofibromatosis 1 pathogenesis
-NF1 is a large gene (350 kb and 60 exons)
that encodes neurofibromin, a protein widely
expressed in almost all tissues but most
abundantly in the brain, spinal cord, and
peripheral nervous system.
-The clinical manifestations result from a
loss of function of the gene product; 80% of
the mutations cause protein truncation.
Issue with neurofibromin
Neurofibromatosis 1 phenotype
- Prenatal onset to late childhood
- Cafe au lait spots
- Axillary and inguinal freckling
- Cutaneous neurofibromas
- Lisch nodules
- Plexiform neurofibromas
- Optic glioma
- Specific osseous lesions
Neurofibromatosis 1 inheritance
autosomal dominant
NF1 Mutation
Neurofibromatosis 1
Myoclonic Epilepsy
with Ragged-Red
Fibers pathogenesis
- In MERRF, the activities of complexes I
and IV are usually most severely reduced.
-The tRNAs mutations associated with
MERRF reduce the amount of charged tRNA
lys in the mitochondria by 50% to 60% and
thereby decrease the efficiency of translation
so that at each lysine codon, there is a 26%
chance of termination.
-Because complexes I and IV have the most
components synthesized within the
mitochondria, they are most severely
affected.
Issue with translation at lysine codon
Myoclonic Epilepsy
with Ragged-Red
Fibers phenotype
-Onset at childhood through adulthood -Myopathy -Dementia -Myoclonic seizures -Ataxia -Deafness
Myoclonic Epilepsy
with Ragged-Red
Fibers inheritance
matrilineal, mitochondrial
Mitochondrial
tRNA lys
Mutation
Myoclonic Epilepsy
with Ragged-Red
Fibers
Marfan Syndrome pathogenesis
-FBN1 encodes fibrillin 1, an extracellular
matrix glycoprotein with wide distribution. -
Fibrillin 1 polymerizes to form microfibrils in
both elastic and nonelastic tissues, such as the
aortic adventitia, ciliary zonules, and skin.
-Mutations affect fibrillin 1 synthesis,
processing, secretion, polymerization, or
stability
Problem with fibrillin
Marfan Syndrome phenotype
- Onset at early childhood
- Disproportionately tall stature
- Skeletal anomalies
- Ectopia lentis
- Mitral valve prolapse
- Aortic dilatation and rupture
- Spontaneous pneumothorax
- Lumbosacral dural ectasia
Marfan Syndrome inheritance
autosomal dominant
FBN1 Mutation
Marfan Syndrome
MCAD Deficiency pathogenesis
-MCAD deficiency is caused by homozygous or compound heterozygous mutations in ACADM. The point mutation c.985A>G, which causes an amino acid change from lysine to glutamate at residue 304 (Lys304Glu) of the mature MCAD protein, is found in approximately 70% of mutant alleles of clinically ascertained patients, but neonatal screening shows over 90 different loss-of-function mutations to date. Change from lysine to glutamate in MCAD protein
MCAD Deficiency phenotype
- Onset between 3 and 24 months
- Hypoketotic hypoglycemia
- Vomiting
- Lethargy
- Hepatic encephalopathy
MCAD Deficiency inheritance
autosomal recessive
ACADM
Mutation
MCAD Deficiency
Lynch Syndrome pathogenesis
-In most colorectal cancers, including in familial adenomatous polyposis, the tumor karyotype becomes progressively more aneuploid -Approximately 70% of Lynch syndrome families with carcinomas exhibiting MSI have germline mutations in one of four DNA mismatch repair genes: MSH2, MSH6, MLH1, or PMS2 Causes tumors and cancer
Lynch Syndrome inheritance
Autosomal dominant
Lynch Syndrome phenotype
- Onset at middle adulthood
- Colorectal cancer
- Multiple primary cancers
DNA Mismatch
Repair Gene
Mutations
Lynch Syndrome
Long QT Syndrome inheritance
Autosomal dominant
or recessive
Long QT Syndrome pathogenesis
-Caused by repolarization defects in cardiac
cells
-Most cases of LQT syndrome are caused
by loss-of-function mutations in genes
that encode subunits or regulatory proteins
for potassium channels
Problem with repolarization (K+ channels)
Long QT Syndrome phenotype
-QTc prolongation (>470 msec in males, >480 msec in females) -Tachyarrhythmias -Syncopal episodes -Sudden death
Cardiac Ion
Channel Gene
Mutations
Long QT Syndrome
Pathogenesis of Hypertrophic
Cardiomyopathy
Approximately 60% of adult and pediatric patients with a family history of HCM will have a sarcomere mutation identified. In contrast, only approximately 30% of patients without a family history will have positive results, often due to sporadic or
de novo mutations
Phenotype of Hypertrophic
Cardiomyopathy
-Onset at adolescence and early adulthood (age 12 to 21 years)-Left ventricular hypertrophy -Myocardial crypts or scarring -Elongated mitral leaflets -Diastolic dysfunction -Heart failure -Sudden death
Cardiac
Sarcomere Gene mutation
Hypertrophic
Cardiomyopathy
Pathogenesis of Hereditary Hemochromatosis
-Mutant HFE interferes with hepcidin
signaling, which results in the stimulation of
enterocytes and macrophages to release iron.
The body, therefore, continues to absorb and
recycle iron, despite an iron-overloaded
condition.
Iron overload
Phenotype of Hereditary
Hemochromatosis
-Onset at 40-60 years in males and after menopause in females -Fatigue, impotence, hyperpigmentation (bronzing), diabetes, cirrhosis, cardiomyopathy -Elevated serum transferrin iron saturation -Elevated serum ferritin level
HFE Mutation
Hereditary
Hemochromatosis
Pathogenesis of Fragile X Syndrome
-The FMR1 gene product, FMRP, is expressed in many cell types but most abundantly in neurons. The FMRP protein may chaperone a subclass of mRNAs from the nucleus to the translational machinery -More than 99% of FMR1 mutations are expansions of a (CGG)n repeat sequence in the 5′ untranslated region of the gene Problem with FMRP in neurons
phenotype of Fragile X Syndrome
- Onset at childhood
- Intellectual disability
- Dysmorphic facies
- Male postpubertal macroorchidism
FMR1 Mutation
Fragile X Syndrome
Pathogenesis of Familial
Hypercholesterolemia
-The LDL receptor, a transmembrane glycoprotein predominantly expressed in the liver and adrenal cortex, plays a key role in cholesterol homeostasis. It binds apolipoprotein B-100, the sole protein of LDL, and apolipoprotein E -Mutations associated with FH occur throughout LDLR; 2% to 10% are large insertions, deletions, or rearrangements mediated by recombination between Alu repeats within LDLR Impacts cholesterol homeostasis
Phenotype of Familial
Hypercholesterolemia
-Onset for heterozygote: early to middle adulthood -Onset for homozygote: childhood -Hypercholesterolemia -Atherosclerosis -Xanthomas -Arcus corneae
Inheritance of Familial
Hypercholesterolemia
Autosomal
Dominant
Low-density
lipoprotein
(LDLR) Mutation
Familial
Hypercholesterolemia
Pathogenesis of Duchenne Muscular
Dystrophy (DMD)
DMD encodes dystrophin, an intracellular protein that is expressed predominantly in smooth, skeletal, and cardiac muscle as well as in some brain neurons -DMD mutations that cause DMD include large deletions (60% to 65%), large duplications (5% to 10%), and small deletions, insertions, or nucleotide changes (25% to 30%) Problem with dystrophin in muscle and neurons
Phenotype of Duchenne Muscular
Dystrophy (DMD)
- Onset at childhood
- Muscle weakness
- Calf pseudohypertrophy
- Mild intellectual compromise
- Elevate serum creatine kinase level
Inheritance of Duchenne Muscular
Dystrophy (DMD)
X-linked
Dystrophin
[DMD] Mutation
Duchenne Muscular
Dystrophy (DMD)
Inheritance of cystic fibrosis?
Autosomal recessive
Inheritance of Deafness
Autosomal dominant
and recessive
Pathogenesis of Deafness
The GJB2 gene encodes connexin 26, one of a family of proteins that form gap junctions -Connexin 26 is highly expressed in the cochlea, the inner ear organ that transduces sound waves to electrical impulses Impacts gap junctions in ear
Deafness
(nonsyndromic) phenotype
-Congenital deafness in the
recessive form
-Progressive childhood deafness in
the dominant form
GJB2 Mutation
Deafness
nonsyndromic
Pathogenesis of cystic fibrosis
Dysfunction of CFTR can affect many
different organs, particularly those that
secrete mucus, including the upper and
lower respiratory tracts, pancreas, biliary
system, male genitalia, intestine, and sweat
glands
Impacts mucus secretion
Autosomal recessive
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
What is the inheritance type?
Difference between x-dominant and x-recessive?
X-dominant all females will be affected. In recessive females will not be affected.
What is variable expressivity?
Variety of expression of one disease within a family.
Autosomal dominant with reduced penetrance
Autosomal recessive
X-linked dominant
Germline mosaicism: Germline mosaicism means that some sperm or eggs have a gene mutation that may not be present in other tissues of the body
Autosomal dominant with imprinting
Digenic: disorder determined by the additive effect of the genotypes at two or more genes from the same parent
Imprinting
In image all of the sons are passing it down. the affected daughter does not pass it down. Only one parent can pass it down. Father and mother would not both pass it down.
How would you rule out a X-linked disorder?
If a father passes down the disease to their son.
Genetic anticipation
A phenomenon in which the signs and symptoms of some genetic conditions tend to become more severe and/or appear at an earlier age as the disorder is passed from one generation to the next.