Exam 2 Flashcards
Loss of function mutation
A type of mutation in which the altered gene product lacks the molecular function of the wild-type gene.
Can be caused by a nonsense or missense mutation
Gain of function mutation
the altered gene product possesses a new molecular function or a new pattern of gene expression
Achondroplasia (ACH), the most common genetic dwarfism in human, is caused by a gain-of function mutation in fibroblast growth factor receptor 3 (FGFR3)
Genotype-phenotype correlation
the association between specific germline mutations (genotype) and the resulting spectrum of disease expression (phenotype)
Allelic Heterogeneity
Different mutations in the same gene affect phenotype
PKU - allelic heterogeneity - different mutations cause different
tolerance of phenylalanine
Mutations Associated with Heterochronic or Ectopic Gene Expression
Mutations in heterochronic genes cause certain cells to adopt cell fates normally associated with earlier or later times in development
“ectopic” expression refers to the expression of genes at locations where the target gene is not known to have a function
Modifier Genes
Mutations/variants in other genes affect phenotype
When does alpha thalassemia start to be observed?
alpha thalassemia seen in utero
Hemoglobin Electrophoresis for Sickle Cell
Thick band for HbS because Autosomal recessive so both copies of beta-hemoglobin express HbS
What happens if you are heterozygous with HbC and HbS?
HbC can be phenotype if paired HbS - so pt 7 probably has some sort of hemoglobinopathies
What determines if condition included in Newborn Screen?
Condition has to be
1) treatable
2) has to be easily identified through test
3) there has to be a benefit to treating before disease is identified ->therefore worth doing right after birth vs waiting for symptoms to arise
Reproductive information about a future pregnancy is not a good reason
sticky clear mucus is a sign of what?
mutations in CFTR
Why does pancreatic insufficiency lead to digestive problems
because digestive enzymes not made
Categories of Metabolic conditions
Amino Acid disorders
PKU
Organic Acidemias
Urea cycle disorders
OTC deficiency
Fatty Acid Oxidation disorders
MCAD deficiency
Mitochondrial disorders
MELAS
mtDNA vs nuclear DNA
Lysosomal storage disorders
MPSs -> know them all
Tay Sachs
Fabry
“Other”
Biotinidase deficiency
Galactosemia
MN CF Newborn Screening Method
If IRT is normal -> STOP
If IRT is elevated -> Genetic Panel Test
If at least one mutation found -> Follow up
sweat test
If Sweat test is >60 mmol/L
Automatic Diagnosis of CF
If sweat test 30-60 mmol/L
Borderline Sweat test
MN CF Newborn Screening Method
If IRT is normal -> STOP
If IRT is elevated top 4% of the day -> Genetic Panel Test
If at least one mutation found -> Considered positive newborn Screen ->Follow up with sweat test
If sweat test 30-60 mmol/L
Borderline Sweat test
Positive Newborn screen
Normal or borderline Sweat test 30-60 mmol/L (Borderline)
1 CF causing mutation or 2 mild CF mutations (e.g. 2 copies of 5T in trans by themselves)
2 5T in trans and borderline
CRMS
Sweat test 30-60 mmol/L (Borderline)
1 CF mutation or 2 possible CF mutations (e.g. 2 copies of 5T in trans by themselves)
But no Positive Newborn screen
CFTR related disorder
POSITIVE sweat test OR 2 cf causing mutations
CF diagnosis
ABSENT OR NEGATIVE NEWBORN SCREEN, fewer than 2 classic cf mutations, and borderline sweat test
CFTR-related disorder
positive newborn screen, fewer than 2 cf mutations, and borderline sweat test
CFTR-related metabolic syndrome
5T on its own in trans
concidered mild mutation of CFTR
CBAVD stands for
Congenital bilateral absence of the vas deferens
How does CF affect the reproductive system?
As the movement of salt and water in and out of cells is altered, mucus becomes thickened. In the reproductive system, the thickened secretions can cause blockages. These can affect how the sex organs develop and work. For most men with CF, the tube (vas deferens) that carries sperm to the penis does not develop.
presentation with F508del and R117H and 5T in CIS
Classic CF
5T on its own in trans
considered mild mutation of CFTR
Poly-T/TG Tract Consequences
worsens phenotype if in CIS with both 5T and R117H mutation
which is worse TG11 or TG13
TG13
Central Nervous System consists of
Brain and spinal cord
Central Nervous System consists of
Brain and spinal cord
R117H and 5T in CIS + TG13
even worse presentation
Two sections of Peripheral Nervous System
1) Autonomic nervous system
Unconscious body functions
2) Somatic nervous system
Conscious control of the muscles
Neuromuscular disorders affect what?
parts of the CNS and PNS
Three types of neuron
1) Sensory Neuron
2)
3)
What does Sensory Neuron do?
Sensory organs
Touch, taste, smell, pain, temperature
What does Interneuron do?
Communication between CNS and the sensory and motor neurons of the PNS
What does Motor Neuron do?
1) Signals from the brain through the neuromuscular junction to the muscles
2) Movement
Three types of neuron
1) Sensory Neuron
2) Interneuron
3) Motor Neuron
most common type of mutation in SMN1 gene
Homozygous deletion of exon 7 in ~ 95% of people (tested on NBS)
How common are de novo deletions in SMA?
2% have de novo deletions in one allele
How common are non deletion mutations in SMA?
3-5% non deletion mutations in one allele, typically with a deletion in the other allele
Will non deletion mutations in SMA be picked up on NBS?
will NOT be picked up on NBS, only deletions
which gene modifies phenotype of SMA but not causative
SMN2 copy number
Reasons father of child with SMA not picked up on with carrier screen?
1) DAD WHO IS SILENT CARRIER, because he has 2 copies of SMN1 in CIS on a single chromosome (most common)
2) den novo mutation (2% of cases - more common than usual because SMN2 is so similar that can get deleted by accident)
3) this dad has non-deletion mutation that is not on carrier screen (3-5% of cases)
Reasons father or mother of a child with SMA not picked up on with carrier screen?
1) parent WHO IS SILENT CARRIER, because he has 2 copies of SMN1 in CIS on a single chromosome (most common) and zero copies on the other -> microarray does not pick this up
2) den novo mutation (2% of cases - more common than usual because SMN2 is so similar that can get deleted by accident)
3) this dad has non-deletion mutation that is not on carrier screen (3-5% of cases)
What other disease besides SMA can occur with a parent who tested negative on carrier screen but kid has disease anyway?
CAH (Congenital adrenal hyperplasia) also autosomal recessive and has the same problem where parent can be SILENT CARRIER, because he has 2 copies of gene in CIS on a single chromosome (most common) and none on the other chromosome
What is the relationship between severity of SMA and SMN2 copy number?
Inverse relationship between severity of SMA and SMN2 copy number
Why do genetic testing in patient with Amyotrophic Lateral Sclerosis (ALS) if it is a clinical diagnosis?
1) Determine familial cause because will effect relatives,
2) Certain variants are appropriate for certain treatment but not others
Symptoms of ALS
Progressive loss of muscle movement
Speech, swallowing, skeletal muscle
ALS weakness is symmetric or asymmetric?
Asymmetric weakness in most cases
limb onset ALS vs bulbar onset ALS
If symptoms begin in the arms or legs, doctors refer to this as “limb onset ALS”
If disease starts affecting speech or swallowing, they call it “bulbar onset ALS”
Familial vs sporadic ALS
“familial” ALS means that there is more than one occurrence of the disease in a family.
“sporadic” when there is no known history of other family members with the disease
“genetic” can apply to both familial and sporadic ALS.
Does ALS always occur with FTD?
Can be isolated or occur in association with frontotemporal dementia (FTD)
What is frontotemporal dementia (FTD)?
Damage to frontal and temporal lobes of the brain
What is the clinical presentation of frontotemporal dementia (FTD)?
Associated with personality, behavior and language
How many susceptibility genes associated with ALS?
> 30 susceptibility genes (and counting)
Most common genetic cause of ALS and FTD?
C9orf72
The expansion of a hexanucleotide (GGGGCC) in C9orf72 is the most common known cause of ALS
Hexanucleotide expansion of C9orf72 seen in familial or sporadic ALS?
Seen in both ~ 40% familial cases and ~ 7% sporadic ca
Age of onset for ALS?
Variable age of onset (20s-90s)
What is the age related penetrance of ALS?
Age related penetrance, almost complete by age 83
Hexanucleotide expansion of C9orf72 seen in familial or sporadic ALS?
Seen in both ~ 40% familial cases and ~ 7% sporadic ca
Does Hexanucleotide repeat expansion repeat number correlate with age of onset, severity or progression of ALS?
No it does not
More does not mean worse, but >30 means ALS
how many Hexanucleotide repeats is considered pathogenic in ALS?
> 30 repeats-pathogenic
What rare event can explain variability in ALS phenotype?
SOMATIC MOSAICISM
Somatic mutations, arising in early embryonic development and leading to mosaicism, have emerged as pathogenic drivers for neurodevelopmental and neurodegenerative disorders. Although these mutations may be absent or undetectable in DNA isolated from peripheral blood, they might be present in subsets of neurons and glia in the CNS, driving diverse clinical outcomes. The much milder clinical phenotype in case 1 might be explained by mosaicism of this mutation in her CNS.
What other gene besides C9orf72 is associated with ALS?
VCP
Mutations in the valosin-containing protein (VCP) gene were recently reported to be the cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases. VCP mutations are known to cause inclusion body myopathy (IBM) with Paget’s disease (PDB) and frontotemporal dementia (FTD).
Duchenne Muscular Dystrophy symotoms
Delayed motor milestones
waddling gait
Gower maneuver
Large calf muscles
Serum CK levels in DMD
> 10x normal
Big Physical sign in DMD
Hypertrophic calf muscles
Serum CK levels in DMD
> 10x normal
When does Cardiomyopathy happen in a child with DMD
teenage years
What are intellectual consequences in some children with DMD?
Some can have mild ID, learning disability, ADHD
When does Cardiomyopathy happen in a child with DMD
teenage years
Median survival with DMD
24 years
CK levels of female carriers of Dystrophinopathies like DMD and Becker?
Elevated
Difference between DMD and Becker?
Later-onset muscle weakness
Serum CK levels in Becker?
> 5x normal
When does Cardiomyopathy happen in a child with Becker?
teenage years
Median survival with Becker?
mid-40’s
Median survival with Becker?
mid-40’s
What is DMD-associated DCM?
Dilated cardiomyopathy (DCM) is a common complication of Duchenne muscular dystrophy (DMD), but it usually does not present with clinically significant symptoms until the later stages of the disease
How does DMD-associated Dilated Cardiomyopathy present?
Left ventricular dilation and congestive heart failure
When do DMD patients present with Dilated Cardiomyopathy?
Males present between ages 20-40
Females present later
Progression is faster in males
if DMD is X-linked why do some females have problems?
Duchenne muscular dystrophy usually affects males. However, females are also affected in rare instances
~15-20% are manifesting carriers and have muscle weakness to some extent.
Female carriers of DMD/BMD
Some can have symptoms:
~15-20% have mild-moderate muscle weakness in adulthood
Can have elevated CK (2-10x normal)
Increased risk for DCM
Is cardiac screening recommended for Female Dystrophinopathy Carriers?
For symptomatic and asymptomatic individuals
Initially in adolescence/ early adulthood or when symptoms begin
At least every 5 years
