Genetics Flashcards
What is uniparental disomy?
person gets 2 copies of gene from same parent
Name syndrome inherited in uniparental disomy?
Chromosome 15
> Angelman
- Angel-MAMA
- loss of maternal copy where dad’s gene usually imprinted (silenced)
= no expression of critical gene
> Prader-Willi
- PAPA-Willi
- critical paternal part missing and maternal part normally imprinted (silenced)
Why do we do DNA testing in kids with CF?
Give parents an idea about prognosis.
Benefit of CF genetic testing:
- dx
- carrier testing
- prenatal genetic dx
- prognostic
Unilateral cleft palate kid. Advice regarding next pregnancy. You advise recurrence risk of?
4%
T or F: biologic parents are thin then child unlikely to be obese.
True.
- Birth wt not predictive; biologic parents predict obesity in child
What is the inheritance pattern for TS?
Autosomal dominant.
2/3 mutation= de novo.
Next child: 50% regardless of gender.
Inheritance pattern of ectopic thyroid:
Sporadic
- Thyroid genesis (including ectopic) usually sporadic.
Dad has hemophilia. Inheritance for future kids?
- 0% of sons
- 50% of daughters carrier
Bckgrd: 1 in 5K males. X linked. Some female carriers with mild bleeding dx (symp)
Child with Tuberous Sclerosis. Mother pregnant and wants to know if next child will have the same?
Recurrence Minimal
- Tub Sclerosis= AD BUT spontaneous mutation in most cases
- if parents (-) for mutation, recurrence risk 2%
Which of the following is AD:
- Tuberous Sclerosis
- Fragile X
- CF
- Hereditary Spherocytosis
- Cong. Adrenal Hyperplasia
- PKU
- Beta thalassemia
- Marfan Syndrome
x Tuberous Sclerosis
x Marfan Syndrome
x Hereditary Spherocytosis (2/3 AD and 1/3 AR)
Fragile X= X linked CF= AR CAH= AR PKU= AR Beta-Thal= AR
T or F: Marfan Syndrome is AR inherited.
False.
AD.
List 5 features of marfan syndrome:
- Ectopia Lentis (lens superior subluxation)
- Pneumo
- Aortic root dilation
- Mitral valve prolapse
- Hypermobility
- Pectus carinatum and pectus excavatum
- Scoliosis
- Arm to Ht > 1.05
- Long fingers
- Wrist and thumb signs
- Pes Planus (Flat feet)
T or F: 1/2 of all hearing loss is genetic.
True.
BUT most non-syndromic
Syndrome: Waardenburg, CHARE, alport, jervell and lange-nielsen (qtc), NF2
T or F: CMV is the most common cause of acquired congenital hearing loss.
True.
List 5 RF for hearing loss:
- TORCH (CMV)
- Low BW
- Apgar 0-4; 0-6 at 5 min.
- Ototoxic med (aminoglycoside, loop diuretic)
- bac meningitis
- Hyperbili
- vent > 5 d
- echo
- head injury
Baby w/ web neck, lymphedema of hand + feet, hypertrophic heart. Dx?
Noonan Syndrome
list 5 traits of noonan syndrome
1. webbed neck Cystic hygroma 2. lymphedema 3. pulmonic stenosis 4. hypertrophic cardiomyopathy 5. crytorchidism 6. short wide set eyes (hypertelorism) 7. Triangular shape with low set eyes 8. early motor delay + LD
How is Turner diff than Nooan:
Female only
L side heart (Coarc, HTN)
++ Renal anomalies (horseshoe kidney for example)
Primary hypogonad (amenorrhea, sterility)
DD less common (Noonan early motor delay + LD)
List 5 traits of William syndrome:
= Gene deletion syn
- Elfin facies (periorbital full, flat nasal bridge, full lips)
- Stellate iris (starburst pattern;= line on inside much lighter; blue green eyes)
- HTN
- Hyper-Ca (irritable, constipation, strong)
- GU (UTI, VUR)
- Connective tissue lax (joint ,scoliosis)
- Very verbal (cocktail party personality)
- Visual-spatial difficulty.
Name CNS finding w/ Sturge Weber Syndrome:
Leptomeningeal angioma.
What is Sturge Weber Syndrome?
- Port wine stain (facial capillary malformation; usually V1 V2)
- Leptomeningeal angioma (abN blood vessel in brain)
CC: stroke like episodes, hemiparesis on opposite side of stain - Glaucoma (abN blood vessel in eye)
T or F: Sturge Weber is inherited.
False.
NOT heritable.
Sporadic mutation in embryo.
T or F: you must do CNS imaging for Sturge Weber.
TRUE
R/O leptomeningeal angioma.
Rocker bottom feet. Cleft palate. AbN ears. Clenched hand with overlapping fingers.
Trisomy 18
Edwards
95% tile. Prominent Ear. Hyper extensible joint. Behaviour problem. Dx?
Fragile X
Large ear, narrow face, big forehead, big testes. Autism DDX.
Tall boy. Delayed puberty. Small firm testes. high pitched voice. Behave and learning issue. Dx?
Klinefelter
XXY
= tall, gynecomastia, hypogonadism, lower IQ, psychiatric dx
- will go through puberty but ALWAYS SMALL TESTES
SUPER BIG HC + big everything + poor tone + DD. Dx?
Sotos Syndrome
White forelock with different colour eyes. Dx?
Waardenburg Syn
- AD
- white forelock
- heterochromia iris or brillant blue
- deaf
- depigmented skin
Suspect Waardenburg Syndrome. Two features. And what next investigation?
- Renal US
- hearing
- echo
- cranial US
Hearing test (R/O deaf)
Waardenburg
- white forelock
- deaf
- heterochromia iris (diff colour) or brilliant blue
What does VACERTL stand for:
V= vertebral defect (i.e. hemi vertebrae) A= anal atresia C= cardiac T= TEF R= Renal anomalies L= limb (usually underdeveloped or missing thumb, hand, forearm)
Imaging: AUS, echo, XR
List two tests for kid suspected with VACERL?
Echo (cardiac)
AUS (renal anomalies)
XR
Microcephaly + Unibrow (synophrys) + long eye lashes + Thin lip. Dx?
Cornelia De Lange
Also: prenatal and postnatal growth delay, proximally placed thumb.
Fragile X. Neurobehav- at risk for?
Hyperactivity
Anxiety
1/3 = ASD traits
Developmental regression. New microcephaly. Abnormal hand movement. Dx?
Rett’s
What is the mnemonic for DiGeorge Syn?
CATCH22
> CHD > AbN facies (narrow palpebral fissure, hooded lids, weird ear, bulbous rectangle shape nose, downturned mouth) > Thymic hypoplasia > Cleft palate > HypoCa2+ (low PTH) > 22q.11.2 deletion
What is a typical feature for achondroplasia?
- proximal limb shortening
- distal limb shortening
- short mid-portion of bone
- non specific shortening
PROXIMAL limb shortening
What are the two genetic Long QT Syndrome?
- Jervell and Lange-Nielsen
(AR; + sensorineural hearing loss) - Romano-Ward
(AD; fhx +; cardiac only)
List four facial dysmorphisms and two clinical feature of FASD.
- microcephalic
- short palpebral fissure
- thin upper lip
- Smooth philtrum
- micrognathia
- Short nose with flattened face
- “Railroad” track ears or other minor anomalies
Two clinical features:
- developmental delay (fine motor, speech)
- Intellectual disability (specific learning impairment- math, reading)
- ADHD
- SGA or growth retardation (ht, length, HC)
What is a common trait of fetal hydantoin son (like maternal phenytoin):
- IUGR
- microcephaly
- cataract
- hypoplastic nail
- sz
Hypoplastic Nail
- Mild Growth delay
- Hypoplasia of distal phalanges
- Syndactyly
- Cardiac anomalies
List 4 things to monitor as part of routine surveillance for T21:
- *CHD (screen at birth)
- Eyes: Strabismus, cataract, nystagmus (annual ophtho then q 2-3 yr)
- Recurrent AOM+ Hearing
- Atlantoaxial subluxation or instability
- OSA
- *Hypothyroid
- *Celiac Dx
- *Constipation
- Growth and Development
T21 hair loss. Most likely Dx and prognosis?
- Alopecia Areata.
- Spontaneous resolution 6-12 mo.
- Recurrence common
- Topical steroid effective in some
List 3 heme dx in kids with T21.
- Neo polycythemia
- Neo leukemoid rxn
- Transient Myeloproliferative rxn
- Anemia
- Leukemia
What is the most common genetic cause of IQ disability?
T21
What is the neo leukomoid rxn vs. transient myeloproliferative dx in T21?
Neo leukmoid:
++ leukocytosis
causing HSM
resolve by self
Transient myelo proliferative dx: as infant myeloblast prolif++ spleen, liver, bone marrow blast on smear WBC high like 40 regress w/in 3 mo but can have hyperleukocytosis, tumour lysis, DIC risk of megakaryocytic leukaemia 1-3 later in 25% of these pt
Turner Dx. Neonatal investigations:
- Karyotype
- Audiology (R/O hearing loss)
- 4 limb BP (R/O coarc)
- Echo (R/O CHD)
- AUS (R/O renal)
- Hip P/E for hip dislocation
Eye at age 1 Teeth at age 2 TSH, T4 at age 4 TTG, IgA at age 4 Obesity > 10 Ovarian f'n by 10
List 2 cardiac complications for Turner:
- Coarc
- Aortic valvular dx (bicuspid aortic valve)
- Hypoplastic L heart
- Cardiac conduction abN
T or F: hyperactivity is associated with Fragile X.
True
T or F: T21 is the most frequent form of inherited intellectual disability.
False.
Fragile X!
Most common genetic cause= T21
When do you test for Fragile X:
- IQ disability
- DD
- Autism
- FHX of Fragile X or undiagnosed intellectual disability
What are girl with CGG permutation (50-200 repeats) at risk of:
- Premature ovarian failure
- Fragile X associated tremor-ataxia syndrome
- neurocognitive deficits
Brother has Fragile X. Should 10 y.o. healthy sister be tested?
Discourage until child able to participate fully in decision to be tested.
- Carrier affect reproductive testing
- But if LD, premature ovarian failure, or Frag X tremor-ataxia sun should test since symptoms
What is the Pierre Robin Sequence Triad:
Micrognathia
+ Glossoptosis (tongue back)
+ Cleft palate
Main concern: feeding, airway
Child with Duchenne Muscular Dystrophy. Inheritance pattern?
X linked
What is diagnostic on biopsy for Duchenne Muscular Dystrophy?
Lack of dystrophin.
Other findings
- endomysial connective tissue proliferation
- scattered degenerating and regenerating myofiber
- increased connectivity btwn muscle fibres
What two things do you want to know to help with genetic counselling for family w/ child with Duchenne?
- what is genetic defective gene specifically?
- does mom have it?
- planning to have more kids?
As can use this info to do targeted testing for carrier or genetic testing on amino/CVS
What is the most common hereditary neuromuscular dx?
Duchenne Muscular Dystrophy.
Poor head lag. Gower’s sign. Pseudo hypertrophy of Calves. Toe walking. Dx? Long term screen require?
Duchenne Muscular Dystrophy.
- Cardiomyopathy
- Scoliosis
- Intellectual impairment/LD
- Pharyngeal weakness (Aspiration)
- Resp wines
Tx: No cure.
Steroids - decrease rate of progression
Hemihypertrophy. Dx?
Beckwith Weidemann Syndrome.
- Macrosomia
- Ear Helical Pits
- Omphalocele
- Low BG (high insulin)
- CA (Wilm’s tumour, hepatoblastoma, neuroblastoma)
T or F: Beckwith Wiedemann Syndrome at risk for cancer.
True.
- Wilm’s
- Hepatoblastoma
- Neuroblastoma
- Adrenocorticoid carcinoma
Regular AUS + alpha-fetoprotein q 3 mo. until 8 y.o. then AUS every 1 -2 yr for kidney stone.
Name one cancer associated with each dx state:
- T21
- Beckwith Weidemann
- Aniridia
T21: Leukemia (specifically acute myeloid leak)
Beckwith Wiedemann: Wilm’s, hepatoblastoma, neuroblastoma
Aniridia: Wilm’s tumour
List three feature so Prune Belly Syndrome:
- Abdo muscle lacking
- B/L undescended testes
- GU abN (VUR; obstructive uropathy risk)
What is the most likely ppt of alpha-1-antitrypsin in children?
Jaundice.
Other: dark urine, steatorrhea, FTT.
Boy with MELAS. what do you tell about passing it on?
MELAS= mitochondrial encephalomyopathy w/ lactic acidosis and stroke-like episode.
- mito.= MOM inherited
- CC: weak, DD, h/a, stroke
- progressive
- No M can pass it on
- F can have affected offspring (M or F) but (+) dad cannot pass it on
Can’t pass NG through nares. List other findings?
Choanal Atresia= Think CHARGE.
> Coloboma (iris, retina)
Heart= Murmur (TOF, AV, canal defect)
Atresia Chooanae
Retarded growth (short)
GU (micropenis, cryptochordism, F hypoplastic puberty)
Ear/Hearing (cup shaped ears, line going across lobe, deaf)
Child w/ DiGeorge. What three things do you investigate/manage?
- Echo and CHD
- Immunodeficiency (CXR for thymic shadow, CBC + diff, T and B cells, immunoglobulin)
- Ca (low Ca2+ and Phosphorous)
- Cleft palate Tx
- Consider AUS for renal hypoplasia (common finding)
- CATCH-22:
- cardiac
- abN facies
- thymic
- cleft palate
- low Ca2+
- 22q11.2
T or F: Rett is usually in M because it is X chromosome dx.
False.
- FEMALE; X linked dominant
- Random X inactivation of MECP2 gene so normal allele in some cells
List 4 features of Rett Syndrome
- Developmental regression (**gross motor delay)
- Acquired **microcephaly
- **Hypotonia
- Autism like (**lose eye contact)
- Lose hand skills, **hand wringing
- Breath holding spells
- **Seizures
- **Ataxia
- ** Scoliosis (progressive)
- Poor wt gain
Giveaway= MIDLINE HANDS!
How do you dx Marfans?
Ghent
= major criteria in 2 system (skeletal, ocular, CVS, genetic)
T or F: Marfan is AD.
True.
List 3 major skeletal diagnostic criteria for Marfans.
- **Pectus carinatum
- Pectus excavatum needing Sx
- **Reduce upper:lower segment AND increased arm:ht
- **Wrist or thumb sign
- **Scoliosis > 20 degree
- Reduce elbow extension
- **Pes planus
Coloboma. Corresponding possible Dx?
CHARGE
- coloboma
- heart (TOF)
- atresia chonanae
- retarded growth
- GU (micropenis, cryptochordism)
- ear/hearing
Dislocated Lens. Name corresponding dx?
Ectopia Lentis…
Marfan: SUPERIOR subluxation
Homocysteinuria= INFERIOR subluxation
Aniridia. Name corresponding Dx.
Aniridia= no iris (no coloured part of eye; just black)
Risk of glaucoma, cataract. Associated w/ Wilm’s tumour.
Dx: WAGR > Wilms > Aniridia > GU > MR
Glaucoma. Name Corresponding Dx.
**Sturge Weber
> port wine
> leptomeningeal angioma
> glaucoma
- *Mucopolysaccharidoses
- *NF1
What is the recurrence risk for T21 in mom with another child with it (47 XY + 21)
No antenatal W/U as recurrence risk 1 %. Until age related risk > 1% (approximate age 40)
Most common form of Down syndrome is what:
Trisomy 21.
4%= translocation
1-2% Mosaicism
** Note higher risk if carrier of balanced translocation. May offer prenatal testing if previous T21 but risk low unless translocation.
In T21 F/U which is most appropriate:
- CBC + smear
- Lipid
- Thyroid F’n
- Hep B serology
- Antigliadin Antibody
Thyroid!
W/in 1st month:
- Karyotype
- Echo
- CBC
- TSH if not newborn screen
Within 6 mo:
- Optho
- Repeat Hearing
- TSH
Annual:
- CBC
- TSH
No XR or celiac; off symptom only
T or F: microcephaly is in Fragile X.
False.
Macrocephaly.
Which condition is associated with macroglossia and umbilical hernia.
- Cong hypothyroid
- Infant DM mom
- Beckwith-Wied
- T21
Beckwith-Wiedemann Syndrome
What ist he triad for Shwachman-Diamond Syndrome?
- Exocrine pancreatic insufficiency
- Neutropenia and other bone marrow
- Bone issue (chondrodysplasia)
Short stature and recurrent infection.
T or F: testicular volume of 15cc help R/O Klinefelter Syn
True.
47XXY
- small firm test
- gynecomastia
- infertility
T21 with vomiting. R/O:
Duodenal Atresia
AXR.
How frequent should AUS be done in kids with Beckwith Wiedemann Syn?
AUS q 3 mo. until 8 y.o. and then annual.
Vascular lesion on face. Severe Thrombocytopenia. What are worried about? What would you find on BW and smear?
Kasabach-Merritt Syndrome:
- Hemang + low plt
- Smear: schistocytes and RBC fragment
- Low fibrinogen, possible anemia
- Can = HF
Most T21 due to 47 XY + 21. Do you need to check parental karyotype?
No.
Recurrence risk 1%
3-4% of Trisomy 21 due to translocation. Do you have to check parental karyotype?
Yes.
Recurrence risk higher than 1%.
A male that looks like Turner. Think of…
Nooan.
What does FISH work well for?
22q11 deletion
Williams
What is Williams Syndrome CHD lesion
Supravalvular aortic stenosis.
What developmental or psych association are with William
Receptive lang delay
Visuospatial
Attention
Anxiety
Who do you remember T13 versus T18?
T13= PaTau= Thirteen
= PPP= Patau, Palate, Midline, Polydactyly
= COARSE features; Midline!
- Holoprosencephaly, cleft palate or lip, CHD, omphalocele, renal anomalies
- usually die within 1st wk of life
T18= Edwards= Eighteen
= Tiny Cute dysmorphic!!
- IUGR, abN ears, clenched hands, rocker bottom feet, abnormal heart + kidney
- short sternum
- early mortality= CHD; late mortality from hypoventilation
How is NF1 inherited
AD
or 50% de novo
Healthy sister of young man with CF wants to start family. Chance o being carrier:
- 5%
- 25%
- 33%
- 50%
- 67%
CF= AR
50% chance carrier
BUT b/c you know by this age she is not affected you remove that form stats and = 2/3
What does genomics imprinting mean?
Gene expressed only from one copy (maternal or paternal) as parental original “marked” by reversible epigenetic mechanism (like methylation)
Child presents with infantile spasms. Top genetic dx on ddx:
- TS
- NF
- Rett Syn
- Angolan
- Tay-Sachs
TS
- autistic like
- infantile spasm
- cardiac rhabdomyoma
List features of T21:
- Hypotonia
- IQ impairment (mod)
- Brachycephaly
- Upslanting palpebral fissure
- Epicanthal fold
- Small Ears
- hearing loss
- short neck with nuchal redundant
- short hands
- single palmar crease
- sandal toe gap
- CHD
- male infertility
- 10%= transient myeloproliferative dx
- increased risk: leukaemia, hypothyroidism, alzheimer’s, myopia
List Turner Features
45XO
- short
- webbed neck
- broad chest + wide nipple
- bicuspid aorta, coarc.
- renal anomalies (horseshoe)
- infertility, ovarian dysgenesis
- visual spatial difficulties
- congenital lympedema
T or F: micro deletion or duplication are detectable by array.
True.
i.e. DiGeorge, Williams, Angelman
How is Sotos inherited?
AD Specific gene mutation Key: - facies (long face, frontal bossing, pointing chin) - learning disability - overgrowth
Which imprinting dx are with chromosome 15 vs. 11?
Imprinting Disorders=
11= Beckwith / Russell Silver
= Hypomethylation
15= Prader Willi/ Angelman
“ PAPA-MAM at 15”
= Deletion
Describe Russell Silver Syn
- IUGR
- relative big head
- triangular face + frontal bossing
- CAM
- 5th finger clindodactyly (sideway bent)
- Low BG
- Normal congition
Cytogenetic tests mean what?
Karyotype
Microarray
FISH
Molecular/DNS testing= everything else.
(i.e. DNA testing for Fragile X)
8 y.o. child heme-vertebrae on XR. Well. Next investigation?
- MRI head
- MRI spine
- AUS
- Echo
AUS
Healthy 8 y.o. with no murmur = AUS
New baby or murmur= Echo
Butterfly vertebae. Make you think of?
Alagille
Sotos versus Fragile X. Differences?
Big everything (VERY BIG)
Prominent chin + Tall forehead + Frontal bossing + Malar Flushing
= DNA gene sequencing
= SOTOS
Upper range in growth
Long face + prominent ear
= DNA PCR testing
= Fragile X
When do you use microarray testing?
For duplication or deletion
- DiGeorge, Williams, Cri Du Chat, and if doing methylation studies (Prader Willi, Angelman)
NOTE: will also pick up things found on karyotype.
For Prader, Anglican, Beckwith or Russell what do you do?
Microarray + Methylation studies..
What testing do you do for Noonans?
Rasopathy
When do you order karyotype?
Trisomy (21, 18, 13) Sex chromosome (Klinefelter XXY, Turner XO)
