Genetics Flashcards
poly-a-tail
100-200 adenines that are located at 3’ end of primary mRNA, involved in mRNA stabilization and allows for mRNA to be exported from nucleus
TAR
AR
Thrombocytopenia (40% mortality from hemorrhage), absent bilateral radii, ulnar abnormalities, normal thumbs
13q deletion
thumb hypoplasia, colobma, retinoblastoma, microcephaly
noonan
AD 12q22
web neck, pulmonic valve dysfunction, cryptoorchidism, abnormal coagulation
What is Fructose 1-6 bisphosphatase deficiency?
impared gluconeogenesis. Presents when glycogen stores are depleted.
hereditary fructose intolerance presentation?
hypoglycemia, hypophosphatemia, liver dysfunction
Due to aldolase B deficiency
cornelia de lange
brachmann-de lange
synophrys, downturning upper lip, micromelia, growth restriction, severe MR, limb defects, cryptorchidism, cardiac defects
beckwith widmann
macroglossia, hemihypertrophy, organomegally, omphalocele, macrosomia, ear lobe creases
hypoglycemia, polycythema
risk of wilms tumor, neuroblastoma and hepatoblastoma
mgmt: monitor with US q3m until 7 yrs, CXR, AFP
prader willi
15q11, Imprinting = variable expression of gene depending on which parent it is inherited from. In PWS:
absent expression of paternal gene, Maternal gene is silenced by methylation.
The paternal gene is not expressed due to
1) 70% microdeletion
2) 20% maternal disomy (both genes which are silent are from mom) - these are less hypopigmented with facies, but more have psychosis later in life
3) imprinting error (the father passed on his mother’s silent gene) - this is much more inheritible
4) balanced translocation
small exteremities, light pigment, cyrptorchidism, hypotonia, micropenis, poor feeding
Dx: DNA methylation will reveal only maternal silenced gene. May need to do fish/karyotype/cma to figure out further details.
Fanconi pancytopenia
AR, increased chromosome breaks in lymphocytes and amniotic fluid cells
Hyperpigmentation, radial hypoplasia, thumb hypoplasia, short, pancytopenia, some MR
35% mortality bc of heme
what should you add to treatment for organic acidemias?
carnitine – helps bind to organic acid and facilitate excretion in urine
advanced paternal age
increases risk for AD musculoskeletal disorders: achondroplasia, apert, marfan, treacher collins, OI, waardenburg
imprinting
silencing of single parent gene that has relevant genetic material on it. Prader willi, angelman, beckwith widermann, russel-silver,
crouzon
AD, FGFR2
more severe than aperts regarding intercranial issues, hydrocephalus, chiari 1 malformation, cerbellar herniation, IC htn
trisomy 13
aka patau
holoprosencphaly, cutis aplasia, microopthalmia, VSD, polydactyly, cleft, persistence of fetal hemoglobin (gowers)
CHARGE
coloboma (may be in back of eye), heart, atresia chonae (50% isolated), retarded growth, GU anomalies, ear anomalies (lop ear). Common to have CN VII palsy. Dx = coloboma/atresia chonae + 3 others
trisomy 18
large occiput, apnea, clenched hands, small mouth, short sternum
What is pyruvate carboxylase deficiency?
Impaired gluconeogenesis. Presents as hypotonia and altered mental status.
achondroplasia
4p16, FGFR3, 80% de novo, AD
MC non lethal chondrodysplasia. homozygous is lethal
short stature, short limbs, triden hand
frontal bossing, flat midface
kyphosis
narrow foramen magnum and c. spinal canal –> hydrocephalus and hypotonia, kyphosis
normal IQ
holt oram
AD cardiac ASD, abnormal thumb, narrow shoulder, upper limb defects
potter syndrome
symptoms due to oligohydramnios, ususally due to renal agenesis and low uop
Menkes syndrome
X linked recessive, xq13
Copper transport leading to deficiency
Kinky hair (light), progressive cerebral deterioration, seizures, wormian bones
Majority death in infancy
Cat eye syndrome
Extra part in 22q11 region
Cardiac, down slanting palpebral fissures, Anal atresia, iris coloboma
thanatophoric dysplasia
fgf3
redundant skin, short limbs, brain stem hypoplasia, hydrocephalus, large cranium
I: curved long bones, flattened vertebrae
II: clover leaf skull
Mass Spec
detection of very small differences in mass of PCR because of variations in DNA sequence.
turners syndrome
short stature, ovarian dysgenesis, broad chest, wide nipples, ear anomalies, cubitus valgus, renal, cardiac. normal IQ. Need estrogen replacement therapy and growth hormone.
apert
aka acrocephalosyndactylyl, FGFR2 mutation
craniosynosotis, syndactyly, broad distal phalynx of first digits, midface hypoplasia, some cognitive impairment
digeorge
microdeltion on 22q11.2 –> abnormal cervical neural crest migration of 3rd and 4th pharyngeal arches/pouches. Hypoplasia of thymus and parathyroid glands –> hypocalcemia, aortic arch abnormalities, facial dysmorphic features (hypertelorism, short palpebral fissures, short philtrum, micro/retrognathia, ear anomalies) cleft), developmental deficiency
PKU: etiology, symptoms, diagnosis
Phenylalanine is unable to be converted to tyrosine.
Phe deposits in the brain, long term causes lower IQ and neuro abnormalities.
Dx: plasma AA will show elevated Phe and Phe:Tyr ratio
Ellis van creveld syndrome
AR. Ectodermal dysplasia
Cardiac, short distal extremities, polydactyly, nail hypoplasia, narrow thorax
Normal intelligence
50% infant death from cardiorespiratory
congenital myotonic dystrophy
ad, myotonin protein kinase gene 19q13, ctg repeat, >45 –> disease, amplification
mother infant dyad
DMK gene
PCR
amplification of specific DNA sequence. DNA is heated and cooled in presence of DNA polymerase (used to copy DNA). Can detect point mutations/deletions.
Mobius sequence
6th and 7th n palsy, myopathy/brain nuclei involvement, expressionless facies, talipes equinovarus, mr
treacher collins
TCOF1 gene
microtia w/ conductive hearing loss, down slanting palpebral fissures, small mandible, airway difficulty, normal IQ, eyelid coloboma
maternal PKU, if untreated, puts the fetus at risk for what?
microcephaly, intellectual disabilities, CHD, IUGR
What are the three kinds of organic acidemia? symptoms? Dx?
Proprionic acidemia, methylmalonic acidemia, levolenic acidemia.
Dx: ketoacidosis, normal to high ammonia because the urea cycle also backs up, bone marrow suppression. Plasma aa will show glycine. Primary anion gap metabolic ketoacidosis.
Carpenter syndrome
AR
Cardiac, polydactyly/syndactyly, later inner canthus, brachycephaly
AR
CF, most IEM, a/b thal, SC disease, 21-hydroxylase def, congenital muscular dystrophy
angelman
15q11, maternal imprinting of mutated component/paternal disomy
blond social, severe MR, low verbal IQ, puppet like moevements, hypotonia, seizure
Meckel Gruber
AR, 17q21
Cardiac, polydactyly, occipital encephalocele, cystic dysplasia kidney
marfan
AD, 15q11, abnormal fibrillin
congenital form: prolapsed valve, aortic dilation, redundant skin, long, die from heart failure.
linkage study
analysis using 2 loci near each other on the same chromosome that are functionally unrelated to detect if patient has intherited chromosome containing a certain disease
oculo auriculo vertebral sequence
from 1st and 2nd branchial arches, includes Goldenhaar normal IQ (IQ is golden) - face hypoplasia, microtia, hemivertebrae
when does OTC present and how do you treat it
within 24-48 hours. males are very sick and newborn first males may die.
tx: ammonia scavengers (phenylbutyrate) and arginine
smith lemli opitz
disorder of cholesterol synthesis
reduced activity of 7-dehydrocholesterol (7DHC) reductase (7DHC –> cholesterol).
anteverted nares, ptosis of eyelids, syndactyly of 2nd and 3rd toes, hypospadias, cryptorchidism, MR, hirschsprung, cong pyloric stenosis
neural tube defects
increased risk with maternal hyperthermia
Microarray
molecular DNA fragments attached to slide –> comparative genomic hybrdization (number of copies of particular gene), microarray expression analaysies (is gene over/under expressed), mutation microarray analaysis (identify mutations or polymorphisms in a gene)
Golden hat
1st and 2nd brachial arch anomalies
Cardiac, facial (malar hypoplasia, malformed ear and tongue, mr, vertebral
Klinefeter
47xxy
Cardiac, long extremities, hypogonadosm, behavior difficulty
Mgmt: testosterone
MSUD: etiology, symptoms, diagnosis
MSUD is when branch chain AA do not break down and accumulate in the body, including leucine, isoleucine and valine. Leucine is particularly toxic to the brain, causing neuro symptoms, cerebral edema and coma. Long term sequelae include decreased IQ.
Dx: plasma AA will reveal leucine, isoleucine, valine and alloisoleucine
X recessive
fabry, hunter, menkes, OCT, g6pd deficiency, wiskot-aldrich, hemophilia A and B, red-green color blindness, Duchennes, ectodermal dysplasia, nephrogenic DI
how do you differentiate between transient tyrosinemia and congenital tyrosinemia
in congenital tyrosinemia, you will have elevated succinylacetone. TT is due to low maturation of 4-OH-phenylpyruvate. It resolves by 4-6 weeks, restrict tyrosine in diet, ? vit C.
CT: due to deficient fumarylacetoacetate. Tx: NTBC
What is the etiology, symptoms and diagnosis of urea cycle defects? Treatment?
An enzyme in the urea cycle pathway is deficient and consequently ammonia is ineffectively metabolized. Ammonia accumulates and deposits in the brain, inducing tachypnea.
Dx: hyperammonemia, respiratory alkalosis. Plasma AA (+) citrulline, arginine, orotic acid.
Tx: includes ammonia scavenging drugs like Na phenylacetate and Na benzoate
williams syndrome
7q11 microdeletion, impacts elastin region
supravalvular aortic stenosis + pa branch stenosis, MR, SGA, feeding difficulty, hypercalcemia, htn, renal anomalies, hypothyroidism, prominent mouth/lips, bulbous nose, stellate iris, hoarse voice
waardenburg
type I-IV abnormal pigmentation (albinism, white forlock), deafness, wide nasal bridge, upper limb defects
AD
protein c/s deficiency, spherocytosis, gilbert, VW disease, contenital myotonic dystrophy, neurofibromatosis, apert, crouzon, hold-oram, marfan, noonan, stickler, treacher collins aplasia cutis, bullous inchythosis/ichthyosis vlgaris, epidermolysis bullosa simplex, keratosis pillaris, partial albinism, peutz-jegher, waardenburg, adult polycystic kidney disease, familial polyposis, gardner, alagille, retinoblastoma, achondoroplasia, OI, tanatophoric dysplasia, postaxial polydactly
What is zellwegers syndrome and how does it present?
It is a peroxisomal disorder. Peroxisomes are responsible for bile acid synthesis, cellular detoxification and oxidation of LCFA. Patients are dysmorphic, similar to trisomy 21 and present with severe hypotonia and liver dysfunction. Also with high forehead. Usually die in first year.
Russel silver
imprinting disease:
Small triangular facies, frontal bossing, short, clinocactyly, IUGR, hypotonia, hypogonadism, limb asymmetry
What is the process of DNA –> RNA
DNA (ACGT) template gets transcribed to primary mRNA via RNA polymerase. Introns get spliced out to mature mRNA. Mature mRNA gets translated to amino acids in ribosomes through tRNA.
fryns syndrome
AR CDH, digital/nail hypoplasia, coarse facies, brain malformations, eye abnormalities, anteverted nares, cleft lip/palate, GI disease, polyhdramnios. Most die perinatally.
cri du chat
partial deletion of 5p
VSD, transverse palmar crease, hypertelorism, downslanting eyes, round face, severe MR, cat like cry from laryngeal abnormality, microcephaly, FTT, hypotonia
Klippel feil
Cardiac, facial (short neck, limited head mvmt, abnormal cervical vertebrae fused, can be associated with sprengel (scapula doesn’t descend)
rubenstein tabi
16p13 microdelition, CREB
downslanting fissures, micrognathia, broad thumbs and toes, increased risk of tumors, eye abnormalities, cardiac
(mish mosh of other syndromes)
lyon hypothesis
that one x chromosome is silenced –> barr body. XO does not have barr body.
What is pyruvate dehydrogenase deficiency?
Impaired ability to create energy from carbohydrates. Pyruvate can move further into Krebs cycle. Presents as hypotonia and basal ganglia damage. Dx: Lactic acidosis, elevated alanine. Only metabolic disorder where you do not want to treat with high glucose.
nonketotic hyperglycinemia
Glycine (excitatory) accumulates in brain. Sz (hiccups). Tx: hemodialysis and benzoate
FISH
single stranded DNA probe tagged with fluorescent marker that is complementary to sequence of interest - exposed to cultured cells. Available for trisomy 13, 18, 21, prader-willi, angelman, cri du chat, digeorge, miller dieker, williams syndrome
MSUD
most concerning complication is cerebral edema, aloleucine and leucine deposit in brain. Thiamine can help.
trisomy 8
campylodactyly, deep palmar creases
most lethal, those that survive are mostly mosaic
stickler
hereditary arthro-opthalmopathy
type II colagen 12q13
flat facies, spondyloepiphyseal dysplasia
Fragile x
X linked dominant, expansion of premutation (cgg repeats) leading to mutation, corresponds to severity
MC cause of MR
loss of function mutation
premutation: 50-200, females may have premature ovarian failure and cognitive deficiets
mutaiton: >200
Long facies, large ears, large testes, autism, connective tissue dysplasia, macrocephaly with structural anomalies
What is galactosemia and how does it present?
Due to a defect in galactose metabolism, GALT activity. Presents with hypoglycemia, cataracts, ecoli sepsis, liver failure (hyperbili) and long term with decreased IQ. Dx: in NBS but need to do it prior to RBC transfusion because the assay is in RBCs. (+) urine non-glucose reducing substances.
Meckel Gruber
17q21, AR, lethal mutation in cilia protein
occipital encephalocele, polydactyly, renal dysplasia –> pulm hypoplasia
DEATH within days
What are specific findings in OTC?
OTC is an X linked urea cycle disorder. Ornithine –> carbamyl phosphate –> X –> citrulline. Due to abnormal ornithine transcarbamylase, there will be an increase in ornithine, decrease in citrulline. Hyperammonemia and respiratory alkalosis.
OI
AD, type 1 collagen defect, COLIA1/COLIA2
I: blue sclera, easy bruising
II: lethal perniatal, most die in utero, delivered with multiple fractures, no benefit of csection, blue sclera
III: progressive, symptomatic by age 2, blue –> white, risk of poor dentitia and hearing
IV:
mgmt: pain management, bisphosphonates
WAGR syndrome
11p13 microdeltion
Wilms tumor, aniridia, GU abnromalities, MR
Fryns syndrome
CDH, agenesis of CC/ DW malformation/ hydrocephalus, cloudy cornea
enhancer
DNA sequence that leads to increased transcription of gene, can be far from relevant gene but coil and come close to promoter, can bind to transcription factors
promoter
a DNA sequence where RNA polymerase binds so transcription can occur (DNA to mRNA), close and upstream to relevant gene
What is FAO defect?
MCAD (C6-10) is the most common. Elevation of fatty acid metabolites due to inability to break down FA. Will present with low ketones. Dx: Plasma acylcarnitine. VLCAD may present with hypertrophic cardiomyopathy, dx elevated c:14:1
what is Fryns syndrome
CDH with CNS, facial anomalies and distal limb hypoplasia
What is Wolf Hirschhorn Syndrome
greek helmet facies (low set ears, micrognathia), seizures, severed MR, septal cardiac defects
1/3 pts die in 1st year of life
what is poland anomaly
syndactyly, chest wall hypoplasia
what is incontenti pigmenti
x linked dominant. fatal in males. four stages of rashes - blistering –> verucous –> hyperpigmented –> hypopigmented. Nemo gene.
What is Lowe syndrome
Intellectual disability, congenital cataracts, hypotonia, renal dysplasia. Oculocrrebral renal syndrome- ocelots gene
neonatal lupus erythematosus (NLE) - what are the common presentations
skin and cardiac. Skin lesions: can present with sun exposure or not, no scarring, usually in first 1-2 months, goes away by 6m as maternal ab go away.
psoriasis - how does it present and what is the treatment
erythematous scaling papules and plaques in diaper area. Differentiate from seborrheic diaper dermatitis.
Treatment: topical emollient and low potency corticosteroid
what are the 3 kinds of epidermolysis bullosa?
Simplex: within epidermis - no scarring. AD. due to keratin defect
Junctional: AR. at junction of dermis and epidermis. Scarring. Due to defect in laminin or integrin or collagin.
dystrophic: deep in dermis. AD and AR. disfiguring scars. AD form in distal extremities.
junctional and AR dystrophic present in neonates
what is massively parallel shotgun sequencing (MPPS)
a way to sequence both mother and fetus at the same time - good for looking at sex chromosome aneuploidy (ie Turners)
what % of Tri 21 get transient myeloproliferative disorder and what is the natural presentation and course?
About 10% of Tri21 get TMD. Most are asymptomatic, but may present with hsm, fibrosis, hydrops. Blasts are high and persist, and may cause anemia and thrombocytopenia, but usually resolve by 3m. Otherwise treat with cytarabine. 20% get AML.
Thought to be due to GATA1 mutation on X chr, it is shorter and involved in hematopoisesis.
northern vs southern dot plots
noRthern: RNA digested and exposed to a DNA probe
southern: DNA digested and exposed to a DNA probe
how are the trisomies inherited
80-90% of tri 13, 18, 21 are complete mutations
5-10% transolocation
1-2% mosaics
what is dennys drash?
progressive renal disease, male pseudohermaphroditism, Wilms tumor
what is pearlman syndrome?
gigantism, overgrowth/visceromegaly, renal hematoma, wilms
what are characteristic features of holt oram
“can’t hold your ASsD”
cardiac, abnormal upper limb anomalies including thumb, ASD
what are lab findings in mevalonic aciduria?
elevated crp, elevated wbc, anemia
atypical for organic acidemia (no acidosis, ammonemia or hypoglycemia)
what are the three types of bladder extrophy complex? (BEEC)
classic, which is mc (60%), bladder inversion, visible urethra, inguinal hernia, ext. genitalia involved
mild, epispadias (30%)
severe, cloacal extrophy (10%)
TMD in tri 21 is a disease of what type of precursor?
megakarycotye
in CHARGE, what are the 4 major criteria?
need 4 major or 3 major, 3 minor.
4 major are ‘4 C’s’:
coloboma, choanal atresia
cranial n. dysfunction, characteristic ears
What is Leigh syndrome?
Mitochondrial disorder, neurodegenerative, curly eyelashes
What is dysplasia vs deformation vs disruption vs malformation
Dysplasia: abnormal organization (achondroplasia)
Deformation: forms normally but then gets messed up (club foot)
Disruption: destruction/interference with normal development (amniotic band)
Malformation: abnormal development (syndactyly)
what gene is responsible for cornelia de lange?
NIPBL, sometimes sporadic, cohesin related genes
assc with synophrisis, gut anomalies*, renal, vertebral/limb anomalies, cranial anomalies
long term outcomes:
ongoing failure to thrive, severe intellectual impairment, hearing loss, pulmonary aspiration, chronic sinusitis, esophageal adenocarcinoma, seizures, problems related to structural cardiac abnormalities, and shortened life expectancy
how do mitochondrial diseases present?
primary lactic acidosis (not secondary to pyuvate metabolism, pyruvate will be normal) –> send whole exome sequencing in addition to metabolic work up
is vacterl an association or syndrome
association (no known genetic linkage)
what are different conditions associated with different fgfr genes?
fgfr1 - pfeiffer (i - 1)
fgfr2 - apert, crouzon
fgfr3 - achondroplasia
what are some organic acidemia associations
MSUD: valine, leucine, isoleucine , assc with thiamine def
isovaleric acidemia: leucine build up
propionic acidemia: isoleucin, biotin helps
PCD: biotin helps
PDD: thiamine, don’t give glucose
also causes BM suppression, hypoglycemia, some hyperammonemia
what are the types of OI?
I: (won) - mild
II: (boo) - perinatal lethal
III: (free from death for now) - progressive
