What is Pharmacogenomics?
The study of gene expression impact on drug pharmacokinetics (how drugs move through the body) and pharmacodynamics (how drugs act on the body)
What is a prodrug?
drugs with little or no function that are transformed into active drugs, active metabolites, excretion pathways, etc.
Pharmacogenomics uses what kind allele nomenclature
star, each allele reflects activity
What gene should be screened prior to the starting of 6-mercaptopurine for ALL
TPMT
What are the effects of some TPMT alleles if they interact with 6-mercaptopurine?
turning off bone marrow
What the KIF6 gene variant is related to metabolism of what drug?
statins
What variants in what gene are associated with statin myopathy?
5/15 in SLCO1A1
CYP2C9 acts as what?
the rate limiting step in the phenytoin metabolism process
CYP2C9 should be utilized to determine what?
The maintenance dose of phenytoin
What combination of CYP2C9 alleles require the lowest reduction of maintenance dose?
2/2
What are potential side effects of a too high phenytoin dose?
prolonged QTc
What allele is related to serious reactions with carbamazepine use?
HLA-B*1502
What reactions can occur with HLA-B*1502 allele and carbamazepine usage?
toxic epidermal necrolysis, maculopapular rash, and Steven Johnson syndrome (life threatening)
T/F: you would expect to see immediate side effects with HLA-B*1502 and carbamazepine usage
False, delayed
What other allele is associated with reactions to Carbamazepine and what populations is it seen in?
HLA-A*3101 and Northern European and Japanese
HLA-B*1502 is related to drug reaction in what other medication?
Fosphenytoin/Phenytoin
What allele is associated with Abacavir and what populations are carriers?
HLA-B*5701; European and Southwest Asian
CYP2D6 metabolizes what types of drugs?
Tramadol (prodrug), analgesics, tamoxifen, antidepressants, antipsychotics, cardiac drugs (100s of drugs)
how do ultra rapid metabolizers respond to prodrugs?
They will have too much of the drug
How do poor metabolizers respond to prodrugs?
They won't have enough of the drug
What gene is associated with malignant hypothermia?
RYR1
What gene is associated with Warfarin usage?
VKORC1
CYP2C19 is associated with what drugs
clopidogrel or plavix
SLCO1B1 is associated with
statins and medications to treat heart disease
Ultrarapid metabolizers can lead to
non-responders to SSRIs
The pituitary gland controls hormone release through
negative feedback
Hormone secretion goes from
hypothalamus to pituitary to endocrine organ to target cells
Growth hormone goes from the pituitary gland to the
liver
What inhibits the release of growth hormones
Somatostatin
What is considered short stature?
height less than or equal to 2 SD below average for sex and age
What is the inheritance pattern of Pallister Hall syndrome and what gene causes it?
AD; GLI3
What are the major features of Pallister Hall syndrome?
hypothalamic hamartomas, imperforate anus, polydactyly, bifid epiglottis, and adrenal insufficiency
What is the triad of septo-optic dysplasia?
Optic nerve hypoplasia, pituitary hormone abnormalities, and midline brain defect
isolated GH deficiency leads to what conditions
Pituitary dwarfism
Isolated GH deficiency Ia is inherited in what manner and caused by what gene?
AR; GH1
Isolated GH deficiency II is inherited in what manner and caused by what gene?
AD; GH1
Laron Dwarfism type 1/Pituitary dwarfism type II is due to what gene and what inheritance pattern?
GHR; AR
Laron Dwarfism type II is due to
post receptor defect in GH secretion (the receptor itself is normal)
Congenital hypothyroidism can cause
Cretinism
What is included in Cretinism?
Severe DD, umbilical hernia, hypotonia
T/F: Congenital hypothyroidism cannot be detected by NBS
False
What percentage of congenital hypothyroidism is caused by thyroid dysgenesis
85%
Thyroid dysgenesis is usually (inheritance pattern) but can be (inheritance pattern, gene)
sporadic; AD (PAX8)
15% of congenital hypothyroidism is due to what?
thyroxine biochemical synthesis pathway
What gene is implicated in thyroxine biochemical synthesis pathway caused congenital hypothyroidism?
SLC5A5 - AR
What is needed for testes to develop?
Testes organizing factor
Congenital adrenal hyperplasia in biological females will lead to
virilization
21 hydroxylase deficiency is caused by
CYP21 gene
What are potential phenotypes of 21 hydroxylase deficiency?
virilizing with salt wasting (null variants leading to decreased cortisol and aldosterone), simple virilizing, and non classical (makes too much testosterone later in life)
Adrenal hypoplasia congenita is caused by what?
Xq21 deletion (containing DAX-1, DMD, GK)
What is the phenotype of Adrenal hypoplasia congenita
acute infantile onset in affected males, childhood onset in 40%, hypogonadotropic hypogonadism that typically manifests in delayed puberty
Duplication of DAX1 can lead to
gonadal dysgenesis in 46, XY individuals
Androgen insensitivity is inherited in what manner?
X-linked
Androgen insensitivity is due to what?
androgen receptor defect
What does Androgen insensitivity result in in biological males
testicular feminization (complete) or atypical genitalia (partial)
Hypoparathyroidism leads to
hypocalcemia
LOF mutations in PTH/PTHrP receptors lead to
Bloomstrand chondrodysplasia
GOF mutations in PTH/PTHrP receptors lead to
Jansen chondrodysplasia
GNAS activating mutations leads to
McCune Albright syndrome
GNAS LOF mutations leads to
Pseudohypoparathyroidism and pseudopseudohypoparathyroidism
The immune systems works both by
cell to cell interactions and release of chemicals to induce reaction
Both B and T cells start in the bone marrow as
progenitor cells
T cells move from the bone marrow to the _______ to the __________
thymus, lymph nodes
B cells move from the bone marrow to the
lymph nodes
Most selection for self tolerance occurs in the
thymus or lymph nodes
B cells are the ______ of the body and _________
worker bees; use antibodies
T cells are the _________ of the body
directors (give directions)
IgM
a sign of a recent infection
IgG
sign there was an infection at some point (crosses the placenta)
IgA
can be found in the mucosa and breast milk
Genetic rearrangements creates a diverse immune system using what mechanisms?
recombination, somatic mutation, junctional variation, and RNA editing
What is the pathophysiology of HIV/AIDs?
The T cells are killed so they can't tell the B cells what to do
X-linked agammaglobulinemia is due to
B-cell deficiency (cannot make IgG)
When would you expect individuals with X-linked agammaglobulinemia to start having infections?
after the first month or two of life (protected by mother's antibodies before then)
What gene causes X-linked agammaglobulinemia?
BTK
What percentage of women with sons with X-linked agammaglobulinemia are carriers?
~80%
What is the most common immunodeficiency?
Selective IgA deficiency (1:500)
Selective IgA deficiency favors
males
What is the presentation of Selective IgA deficiency?
recurrent infections, associated with autoimmune diseases, moderately increases risk of GI cancer
What is the presentation for Hyper-IgM
recurrent infections, chronic diarrhea, anemia, associated with lymphoma, autoimmune disorders, liver disease
What is the inheritance pattern of hyper-IgM
X-linked, AR, or rarely AD
What condition can hyper-IgM accompany?
ectodermal dysplasia (IKBKG)
AD-HIES (Job syndrome) is caused by what gene?
STAT3
What is the classic triad of AD-HIES (Job syndrome)?
Recurrent skin boils, cyst-forming pneumonia, and extreme elevations of serum IgE
Severe Combined Immunodeficiency (SCID) is due to
a low number of T cells which causes the B cells not to work
SCID is fatal by what point if not treated?
1 year
SCID can be inherited in what manner?
AR and X-linked (IL2RG)
How is SCID treated?
bone marrow transplant
Wiskott-Aldrich syndrome is inherited in what manner and caused by what gene?
X-linked and WAS
What is the triad associated with Wiskott-Aldrich?
low platelet counts, eczema (80%), recurrent infections (especially ear)
What are the symptoms of ataxia telangiectasia?
begins with ataxia, develops telangiectasias (typically starts on the ears), recurrent infections, poor growth, increased risk of leukemia/lymphoma
Type 1 Griscelli syndrome results in
silvery-gray sheen of the hair, hypopigmentation of the skin, and neurologic impairment
Type 2 Griscelli syndrome results in
silvery-gray sheen of the hair, hypopigmentation of the skin, and immunologic impairment
Type 3 Griscelli syndrome results in
cutaneous features only
Griscelli syndrome is more prevalent in what groups?
Turkish and Mediterranean
Chediak-Higashi syndrome is inherited in what manner and caused by what gene?
AR, LYST
What are the major findings of Chediak-Higashi syndrome?
partial oculocutaneous albinism, bacterial infections of the skin and respiratory tract, mild bleeding tendency, cognitive impairment, peripheral neuropathy, ataxia, parkinsonism
Shwachman Diamond syndrome is inherited in what manner and caused by what gene?
AR, SBDS
What are the symptoms of Shwachman Diamond syndrome?
Neutropenia, recurrent infections, anemia, thrombocytopenia, increased risk of developing myelodysplastic syndrome, AML, and aplastic anemia, pancreatic insufficiency, fatty, foul smelling stools (steatorrhea), FTT, skeletal abnormalities (narrow rib cage and short ribs), DD
T/F: Adams-Oliver syndrome is inherited in an AR manner
False, both AD and AR
What are the symptoms of Adams-Oliver syndrome?
cutis aplasia (missing skin on the top of the head), abnormal nails, syndactyly, brachydactyly, or oligodactyly (missing digits), cutis marmorata telangiectatica (disorder of the blood vessels that causes a reddish or purplish net like pattern over the skin), pulmonary hypertension, ID, limb defects
Johanson-Blizzard syndrome is inherited in what manner and due to what gene?
AR, UBR1
What are the major features of Johanson-Blizzard syndrome?
hypoplastic nasal alae, short stature, short nose, SNHL, oligodontia and microdontia, microcephaly, ID, pancreatic insufficiency, cutis aplasia
Incontinentia Pigmenti is inherited in what manner and due to what gene?
X-linked dominant, IKBKG
T/F: Incontinentia pigmenti is often lethal in males
True
What is the de novo rate of IP?
~60%
De novo mutations are more likely ______ in IP
Paternal
What is the presentation of IP?
babies will have blisters and the blisters will scab over and form whirls, streaky or whirled hyperpigmentation, missing or supernumerary nipples, alopecia, lined or pitted fingernails and toenails, pigment changes of the eyes, dental abnormalities, may affect the brain (most people do not have ID however)
Focal dermal hypoplasia is inherited in what manner and caused by what gene?
X-linked dominant, PORCN
T/F: Focal dermal hypoplasia affects both sex equally
False, lethal in non mosaic males
What are the symptoms of focal dermal hypoplasia?
areas of hyper and hypopigmentation, atrophic skin, sparse or absent hair, dysplastic/hypoplastic/ridged nails, and limb abnormalities
Ocular albinism is inherited in what manner and caused by what gene?
X-linked, GPR143
What percentage of carriers of ocular albinism will have decreased pigment?
80-90%
What is the presentation of ocular albinism?
hypopigmentation of the iris and retina, decreased visual acuity, decreased depth perception (stereoscopic vision), nystagmus, strabismus, photophobia, minor pigmentation differences
T/F: vision loss worsens over time in those with ocular albinism
False
Oculocutaneous albinism is inherited in what fashion
AR
Type 1 oculocutaneous albinism is caused by what gene?
TYR
OCA1A results in
white hair, non-tanning skin, fully translucent eyes that do not darken with age
Which form of OCA1 is more pigmented?
OCA1B
OCA type 2 is more prevalent in what population?
Southern African (Bantu speaking) 1:3700
OCA type 3 is more prevalent in what population?
Southern African (1:8500)
OCA type 3 is caused by what gene
TYRP1
What is the phenotype of OCA type 3?
can result in reddish pigmented hair overtime
OCA type 2 is caused by what gene
OCA2 (on chromosome 15 in the region with PWS and Angelman)
OCA type 4 is most common in what population
Japanese
Hypomelanosis of ito is characterized by what?
pigmentary mosaicism resulting is a swirl like pattern, facial dysmorphic features, irregularly shaped teeth, macrocephaly, can have CNS abnormalities and ID, hair findings
T/F: most cases of hypomelanosis of ito are sporadic
true
T/F: there is an inflammatory stage in hypomelanosis of ito
False
Most cases of hypohidrotic ectodermal dysplasia are inherited in what fashion
X-linked recessive
What are the signs of hypohidrotic ectodermal dysplasia in males?
sparse light hair, absence of teeth, decreased ability to sweat, heat intolerance, ear wax impaction, dry secretions, normal nails
What genes are associated with X-linked hypohidrotic ectodermal dysplasia?
EDA
What are the signs of hypohidrotic ectodermal dysplasia in females?
No to mild symptoms. Peg shaped teeth, absence of a few teeth, patchy sweating, mild sparse scalp hair, between 60-80% of carrier females will have hypodontia (missing teeth except for 3rd molars)
T/F: hypohidrotic ectodermal dysplasia can be AD or AR
True
What genes are associated with AD or AR hypohidrotic ectodermal dysplasia?
EDAR and EDARADD
Hidrotic ectodermal dysplasia type 2 (Clouston syndrome) is inherited in what manner?
AD
HED type 2 (Clouston syndrome) is caused by what gene
GJB6
HED type 2 p.Gly11Arg mutation is found in what populations?
French, French Canadian, African, Spanish, Scottish, Irish , Chinese
HED type 2 p.Ala88Val is found in what populations?
Indian, Malaysian, and Welsh
HED type 2 p.Asp50Asn is found in what population
AJ
HED type 2 p.Val37Glu is found in what population?
Scottish
What are the symptoms of HED type 2 (Clouston syndrome)
Normal sweating, partial or total absence of hair, nail hypoplasia and nail deformities, finger clubbing, skin hyperpigmentation over joints, normal teeth, thickened skin on palms and soles
Ellis van Creveld syndrome is inherited in what pattern and caused by what genes?
AR, EVC,EVC2
What is the presentation of Ellis van Creveld?
dwarfism (short forearms and lower legs), narrow chest with short ribs, polydactyly, malformed fingernails and toenails, ectodermal dysplasia
Ectrodactyly-Ectodermal dysplasia Cleft lip/Palate (EEC) syndrome is inherited in what manner?
AD
What is the most common type of EEC syndrome and what gene is it caused by?
Type 3 (90% of cases), TP63
What are the features of EEC syndrome?
ectodermal dysplasia, ectrodactyly, and clefting
X-linked ichthyosis typically presents at what point
birth
What gene causes X-linked ichthyosis?
STS gene (90% complete or partial deletions)
What are the symptoms of X-linked ichthyosis ?
Large, dark scales on the body, palms and soles are normal, steroid sulfatase deficiency, teeth abnormalities, sparse hair, opaque corneas (25%)
Decreased estriol levels can be in indication of what two conditions in pregnancy?
Smith-lemli-opitz and X-linked ichthyosis (steroid sulfatase deficiency)
Congenital ichthyosis is most often inherited in what pattern?
AR
What are the symptoms of Congenital ichthyosis?
erythroderma with fine white scales (improves by puberty), large plate-like scales and ectropion, wide spectrum of severity
What is the most common cause of congenital ichthyosis?
TGM1
Congenital ichthyosis is more common in what patient population?
Norwegian
Harlequin ichthyosis is inherited in what manner and caused by what gene?
AR, ABCA12
What is the presentation of harlequin ichthyosis?
premature birth, very hard thick skin covering the body, skin forms diamond shaped plates that are separated by fissures, affected infants have feeding problems, difficulties controlling water loss, regulating body temperature, and fighting infections, respiratory problems and dehydration
Lamellar ichthyosis is most often caused by what gene and inherited in what pattern?
TGM1 (90%) and AR
What is the presentation of lamellar ichthyosis?
tight, clear sheath covering the skin at birth, scaly skin, eyelids and lips turned outward, alopecia, nail dystrophy, hypohidrosis, increased sensitivity to heat
Congenital Ichthyosiform Erythroderma (CIE) is inherited in what pattern and caused by what genes?
AR, ABCA12, ALOX12B, ALOXE3
What is the presentation of congenital ichthyrosiform erythroderma?
red skin covered with fine white scales, palmoplantar keratoderma, anhidrosis, nail dystrophy
What is the inheritance pattern and the genetic causes of Resfum disease?
AR, PHYH (90%) and PEX7
What are the symptoms of Refsum disease?
RP, anosmia, bone abnormalities of the hands and feet, ichthyosis, ataxia, and hearing loss
Pregnant people's blood volume is increased by what percentage?
30-50%
Which type of cells make up the greatest number in the body?
RBC (84%)
T/F: mature red blood cells lose their nuclei
true
HbF (fetal hemoglobin) is
a2Y2
Persistent fetal hemoglobin can lessen the symptoms of what condition?
sickle cell
What populations have a higher rate of B-thal?
Mediterranean (highest incidence in Cyprus and Sardinia), Middle East, Transcaucases (Albania and Georgia), Central Asia, Indian Subcontinet
B-Thal can either be caused by
point mutations in the B-globin genes or deletions of the B-globin gene cluster which includes (gamma, delta, and beta)
B-thal trait or B-thal minor occurs when
there is one non working copy of the Beta globin gene - either completely nonworking copy or reduced amount
B-thal intermedia occurs when
there is a combination of LOF copies and reduced function copies (B0/B+, B+/B+, BE/B+, BE/B0)
Hemoglobin E is caused by a
single point mutation in the Beta globin gene (E26K)
What populations is hemoglobin E seen in most frequently
Southeast Asian, Northeast Indian, Sri Lankan and Bangladeshi descent
B-thal major (Cooley's anemia) is cause by what?
Two null variants of the Beta globin genes (B0/B0)
What are the symptoms of Beta thal trait?
Asymptomatic, mild microcytic hypochromic anemia
What are the features of B- thal intermedia?
variable severity, mild to moderate anemia, possible extramedullary hematopoiesis, iron overload (rarely require transfusion)
What are the features of B-thal major?
Presents in infant or child <2 years with severe microcytic anemia, hepatosplenomegaly, FTT, transfusion with chelation dependent.
What is the most curative option for B-thal?
bone marrow transplant
If B-thal goes untreated, what can it result in?
FTT, jaundice, pallor, poor musculature, enlarged liver and spleen, skeletal changes (hyperproliferation of the bone marrow to produce more cells causing expansion of the bones)
What blood test results would indicate B-thal?
MCV 50-70, MCH 12-20, and Hb <7
What is considered a normal MCV?
81
What blood test results would indicate a B-thal carrier?
MCV <81, MCH 18-22, and Hb of 11-14
What is considered a normal MCH?
27.5- 33.2
What is considered normal Hb for males?
14-18
What is considered normal Hb for females?
12-16
What hemoglobin pattern would you expect for someone with B-thal major?
95-98% HbF, 2-5% HbA2, and 0% HbA
What hemoglobin pattern would you expect for someone with B-thal intermedia?
70-90% HbF, 10-30% HbA, variable HbA2 depending on other 2 values
What hemoglobin pattern would you expect for a carrier of B-thal?
.5-4% HbF, >3.5% HbA2, and 92-95% HbA
Alpha thal is most common in what parts of the world?
Africa, mediterranean, middle east, southeast asia and pacific
Individuals of Asian ancestry typically have their alpha thal mutations in what configuration?
cis (--/aa)
What is the rate of alpha thal trait in the Asian population?
>1/20
In the Mediterranean population, what is the rate of silent carriers of Alpha thal (-a/aa)?
1/30-1/50
T/F: Cis mutations are also seen in the Mediterranean population when it comes to alpha thal
True
What is a-/a- carrier rate in Black Americans?
1/30-1/50
T/F: Trans mutations are more commonly seen in the African population in regard to Alpha thal
True
A-thal-2 or asymptomatic silent carriers have what genotype?
a-/aa
A-thal-1 or a-thal trait has what genotype?
a-/a- or --/aa
HBH disease has what genotype?
a-/--
HbBarts has what genotype?
--/--
What is the phenotype of A-thal-2 (asymptomatic silent carrier)
asymptomatic
What is the phenotype of A-thal-1 (alpha thal trait)?
Can have some mild microcytic anemia
What is the phenotype of HBH disease
reduced HbA production (25-30% total), HBH is B4 (the remaining beta globin) which destroys red blood cells, can have a severe presentation with hepatosplenomegaly, skeletal changes, and mild to moderate anemia, jaundice, leg ulcers, gallstones, infections, folic acid deficiency
T/F: individuals with HBH disease typically do not live into adulthood
False
HbBarts often presents _________ and is typically _______
prenatally, fatal
HbBarts results in what type of hemoglobin
4 gamma globin units
What is the phenotype of HbBarts?
premature infant or death in utero, pallor, edematous friable placenta, massive hepatosplenomegaly, hydrops fetalis
Laboratory values for a-/aa are
Normal Hb, Normal retics, MCV 75-80, and MCH 26
Laboratory values for -a/-a or --/aa are
Normal Hb, Normal retics, MCV 65-75, and MCH 22
Laboratory values for -a/-- are
Hb 7-10, retics 5-10%, MCV 55-65, and MCH 20
Laboratory values for --/-- are
Hb 4-10, - retics, MCV 110-120, MCH -
What type of alpha thal are you likely to see an increased number of reticulocytes (immature red blood cells)?
HbH disease
Sickle cell results from what change in the beta globin gene most often?
p.Glu6Val
What are the complications of sickle cell disease?
hemolytic anemia, painful crises (ischemic pain), infarction in spleen, CNS, bones, liver, kidneys, and lungs, venous obstruction of organs, increased susceptibility to infections, acute chest syndrome (cells become clumped together in lungs)
What is the median life expectancy for sickle cell disease?
42 y for males, 48 years for females
What Hb electrophoresis results would you expect to see with sickle trait?
S/A 40/60
What is the most severe type of sickle cell?
HbSS
What blood test and Hb electrophoresis findings would you expect to see in sickle cell SS?
Hb 7-10, MCV 80-100, S/A: 100/0, HbF 2-25%
What is the presentation of HbS/B0
Vasocclusion, aseptic bone necrosis
What blood test and Hb electrophoresis findings would you expect to see in HbS/B0
Hb 7-10, MCV 60-80, S/A 100/0, HbF 1-10%
T/F: the phenotype associated with S/thal+ is rare crises
True
What blood test and Hb electrophoresis findings would you expect to see in HbS/B+
Hb 10-14, MCV 70-80, S/A 60/40
What is the phenotype of Sickle Cell HbSC
Rare crises and aseptic necrosis, painless hematuria
What blood test and Hb electrophoresis findings would you expect to see in HbS/C
Hb 10-14, MCV 80-100, S/A 50/0, C 50%
Hereditary spherocytosis is most often inherited in what fashion?
AD (75%)
What percentage of hereditary spherocytosis is sporadic?
1/4
Mutations in what account for 50% of hereditary spherocytosis?
Ankyrin ( type II)
Spectrin (type I) mutations account for what percentage of hereditary spherocytosis?
25%
Spherocytes cause what kind of complications?
splenaomegaly, anemia, iron overload, aplastic anemia after parvovirus, jaundice, gallstones
What is the cure for hereditary spherocytosis?
Splenectomy; typically delayed until age 5 in order to decrease incidence of encapsulated bacterial infection
Protein C deficiency is inherited in what manner?
AD
Protein C deficiency is associated with what locus?
2q13-14
Homozygotes and compound hets for protein C deficiency present with
massive venous thrombosis in the neonatal period, purpura fulminans (burst blood vessels) in newborns, ~50% severe symptoms
Heterozygotes for protein C deficiency can present with
DVT, PE, superficial phlebitis <40 years, cerebral thrombosis, skin necrosis after anticoagulant therapy, and 8-10x risk for thrombosis
How is protein C deficiency diagnosed?
protein C levels with normal coagulation tests
Factor V leiden is caused by mutations in what gene?
F5
What change in F5 is seen at a 6% frequency in the white population?
c.1691G>A (p.Arg506Gln)
What is the risk for heterozygotes with a FV Leiden mutation?
3-8x risk for thrombosis
What is the risk for homozygotes with a FV Leiden mutation?
18-80x risk of thrombosis
What are prenatal risks associated with FV Leiden?
increased risk of pregnancy loss, IUGR, preeclampsia, and abruption
Hemophilia A is inherited in what manner and caused by what gene?
X-linked, F8
T/F: Prothrombin G20210A allele has very variable expression
True
Prothrombin G20210A allele increases the risk for thromboembolism by what in adults and by what in kids?
2-4x, 3-5x
What percent of mothers of sons with hemophilia A are carriers?
80%
What percentage of women with a pathogenic variant in F8 are symptomatic?
10%
What is the incidence of Hemophilia A
1 in 4000
What are the symptoms related to Hemophilia A?
prolonged oozing after injuries, tooth extractions, surgery, renewed bleeding, and delayed bleeding. Spontaneous bleeding can be seen in severe forms.
What is considered normal FVIII clotting activity
50-150%
Severe Hemophilia A is classified by what clotting activity?
<1%
Moderate Hemophilia A is classified by what clotting activity?
1-5%
Mild Hemophilia A is classified by what clotting activity?
5-35%
Severe hemophilia A is caused by
gene inversion in intron 22 (50%) or intron 1 (2-3%), large deletions, insertions, frameshift, splice junction
Mild to Moderate Hemophilia A is caused by
primarily missense mutations
Hemophilia B is caused by what gene?
F9
T/F: Hemophilia B is clinically indistinguishable from hemophilia A
True
T/F: Germline mosaicism is in hemophilia B
True
Familial Mediterranean fever is inherited in what pattern and caused by what genes?
AR, MEFV
What are the symptoms of familial Mediterranean fever?
Autoinflammatory disease, AA amyloidosis, recurrent febrile episodes with peritonitis, synovitis, and/or pleuritis, recurrent erythema, elevated serum fibrinogen, kidney failure may occur from prolonged amyloidosis
What is the treatment for familial Mediterranean fever?
Preventative oral colchecine
Fryns syndrome is inherited in what manner?
AR
The major features of Fryns syndrome include
Diaphragmatic hernia, distal digital hypoplasia, significant pulmonary hypoplasia, death in neonatal period, coarse facial features, polyhydramnios, corneal clouding, renal dysplasia, brain malformation
Goldenhar syndrome is inherited in what fashion?
AD
What are the major features of Goldenhar syndrome?
hemifacial microsomia (incomplete development of the ear, nose, soft palate, lip, and mandible), limb dermoids (teratomas), preauricular skin tags, heart, kidney, and lung underdevelopment/agenesis (typically unilateral), unilateral hearing and vision loss
Greig cephalopolysyndactyly syndrome is typically inherited in what manner and caused by what genetic change?
AD, GLI3 gene or 7p13 microdeletion
Greig cephalopolysyndactyly syndrome presents with
macrocephaly, hypertelorism, pre and post axial polydactyly, cutaneous syndactyly (often toes 1,3 or fingers 3,4)
Hay Wells syndrome (AEC syndrome) is inherited in what manner and caused by what gene?
AD, TP63
What are the major features of Hay Wells syndrome (AEC syndrome)?
Ectodermal dysplasia, complete or partial fusion of upper and lower eyelids, sparse wiry hair, skin erosions, pigmentary changes, nail changes, abnormal teeth, hypohidrosis, ectrodactyly
Holt-Oram syndrome is inherited in what manner and caused by what gene?
AD, TBX5
What are the major features of Holt-Oram syndrome?
Wrist bone abnormalities, partial or complete absence of forearm bones, missing limbs, limb reduction, underdeveloped bones, CHDs (ASD is most common and 75% have a heart problem of some sort), increased susceptibility for cardiac conduction disease
What medication exposure is a phenocopy of Holt-Oram syndrome?
Thalidomide
What gene causes AD Kabuki syndrome?
KMT2D
What gene causes X-linked Kabuki syndrome?
KDM6A
What are the features of Kabuki syndrome?
Mild to moderate ID, DD, CHDs, hearing loss, arched eyebrows, long eyelashes, long palpebral fissures, flat broadened nasal tip, large protruding earlobes, microcephaly, seizures, short stature, scoliosis, persistent fetal finger pads
L1 syndrome is inherited in what manner and caused by what gene?
X-linked, L1CAM
T/F: There is a spectrum of phenotypes associated with L1 syndrome
True
T/F: MASA is the most severe phenotype of L1 syndrome
False, HASA
What are the major features of X-linked hydrocephalus Major (HASA)
Severe, prenatal onset hydrocephalus, Severe ID, adducted (clasped) thumbs, spasticity, stenosis of the aqueduct of Sylvius
What are the major features of MASA syndrome?
Mild to moderate ID, Aphasia, Spastic paraplegia, adducted thumbs, brain MRI abnormalities
What are the major features of SPG1 (X-linked complicated hereditary spastic paraplegia 1)
mild to moderate ID, spastic paraplegia, normal MRI
Progeria is caused by what gene and inherited in what manner?
LMNA, AD
What are the major features of Progeria?
FTT, Scleroderma like skin lesion, full body alopecia, large head with prominent scalp veins, wrinkled/aged facial appearance, kidney failure, loss of vision, musculoskeletal deterioration, severely shortened lifespan (typically teens/twenties)
Pseudoxanthoma Elasticum (PXE) is inherited in what manner and caused by what gene?
AR, ABCC6
What are the major features of PXE?
pseudoxanthomas in the eyes, skin, and blood vessels, premature atherosclerosis, peau d'orange on ophthalmologic exam, GI bleeding, muscle pain, increased risk for MI
Rett syndrome is typically inherited in what manner?
X-linked dominant
Rett syndrome is caused by what gene?
MECP2
What are the major features of Rett syndrome?
normal development followed by psychomotor regression beginning around age 2, which eventually plateaus, partial or complete loss of purposeful hand skills, partial or complete loss of spoken language, impaired or absent walking ability, hand stereotypies, severe ID, sleep disturbances, diminished pain response
Septo-Optic dysplasia includes what features?
optic nerve hypoplasia leading to nystagmus and poor vision, pituitary hypoplasia/dysfunction that leads to growth hormone deficiency and absence of hormone production, midline brain anomalies (absence or underdevelopment of the cavum septum pellucidum an/or absence or underdevelopment of the corpus callosum)
What proportion of individuals with septo-optic dysplasia have all three major features?
1/3
Thrombocytopenia with absent radius (TAR) is inherited in what manner?
AR
What are the major features of TAR?
Thrombocytopenia, congenital absence of the radius, joint problems, heart problems, GU anomalies
Wolfram syndrome is inherited in what pattern and caused by what gene?
AR, WFS1
What are the three major features of Wolfram syndrome?
childhood onset diabetes, optic atrophy, and deafness
What qualifications does someone have to meet in order to be diagnosed with epilepsy?
Having 2 or more unprovoked seizures more than 24 hours apart or 1 unprovoked seizure and a risk of additional seizures (such as an abnormal EEG)
What is the incidence of epilepsy?
1 in 26
What percentage of seizures are considered idiopathic and thought to have a genetic cause?
75%
The ILAE classification epilepsy has three levels for classifying epilepsy. How does the classification work?
seizure type to epilepsy type to syndromic diagnoses
T/F: Dravet syndrome is one of the most common epilepsy syndromes
True
80-90% of __________ is caused by variants in the SCN1A gene
Dravet syndrome
What genes cause Dravet like syndrome?
PCDH19, GABRG2, SCN1B
Dravet syndrome typically follows what inheritance pattern
AD
T/F: Dravet syndrome is typically inherited
False, de novo
What is the clinical presentation of Dravet syndrome?
seizure onset within first year (typically 6 months), febrile seizures that progress to afebrile seizures, hemiclonic or tonic clonic seizures, status epilepticus, normal development leading to developmental plateau and ID
What genes are implicated with Febrile seizures/Febrile seizures plus/Genetic epilepsy with Febrile seizures plus (GEFS+)?
SCN1A, SCN1B, GABRG2
T/F: GEFS+ exhibits AD inheritance with full penetrance
False, reduced penetrance
What is the clinical presentation of Febrile seizures?
Tonic clonic seizures associated with fever occurring between 3m-6y
When is a febrile seizure considered atypical?
if it extends past the age of 5-6 years
What is the presentation of Febrile seizures +?
FS that extend beyond the typical range of febrile seizures and/or the occurrence of both febrile and afebrile generalized tonic clonic seizures
What is the presentation of GEFS+
Familial epilepsy syndrome in which affected individuals within a family typically have a variety of epilepsy phenotypes, varying from simple febrile seizures and febrile seizures plus with a good outcome to severe epileptic encephalopathies
T/F: GEFS+ typically has a cognitive impact
False
Ohtahara syndrome is typically inherited in what manner?
AD
Ohtahara syndrome is typically
de novo
What genes are associated with Ohtahara syndrome?
STXBP1, KCNQ2, SCN2A
What is the clinical presentation of Ohtahara syndrome?
Tonic seizures and infantile spasms beginning from 0-3 months, burst suppression on EEG, DD, severe ID, developmental and epileptic encephalopathy, typically non verbal and non ambulatory
Self limited infantile epilepsy (Benign familial neonatal/infantile epilepsy) is inherited in what manner?
AD with reduced penetrance
What genes are associated with self limited infantile epilepsy?
KCNQ2, SCN2A, PRRT2
What is the clinical presentation of Self limited infantile epilepsy?
Seizure onset within first month (can be focal or generalized), resolve within a few months, no associated developmental concerns
Progressive myoclonic epilepsies are
a group of 10 rare types of epilepsy that are progressive. People with PME have a decline in motor skills, balance, and cognitive function over time
T/F: individuals with PMEs are typically normally developing until the seizures start
True
PMEs are typically inherited in what manner?
AR
Unverricht-Lundborg disease is what type of condition
progressive myoclonic epilepsy
T/F: Individuals with Unverricht-Lundborg disease typically die in childhood
False, they typically live into adulthood and if they respond well to treatment, they can have a normal life expectancy
What gene causes Unverricht-Lundborg disease?
CSTB
Neuronal ceroid lipofuscinoses (NCLs)/Batten Disease is characterized by
Normal development until 4-6 years and then vision impairment via retinal degeneration, ID, myoclonus, epilepsy, developmental regression including losing the ability to speak full sentences and walk independently
What is the life expectancy of someone with NCLs/Batten Disease?
~10 y
What gene is related to Batten Disease/NCLs?
TPP1
What is the treatment for Batten Disease/NCLs?
ERT called Brineuria that replaces the TPP1 enzyme. Biweekly infusions directly into the ventricles of the brain are needed
What testing methodology has the highest yield for epilepsy syndromes?
WES (30-50%)
How do Anti-Sense Oligonucleotides (ASOs) work?
They are small strands of DNA that bind to RNA in a sequence specific manner. They can either upregulate normal proteins incases of haploinsufficiency or downregulate mutant proteins