Genetics Flashcards
What is the FISH study and what is it used for?
Synthesis of a single-stranded DNA primer that is complementary to the sequence of interest, tagged with fluorescent marker–> visible using UV light
Used to identify presence/absence of a specific sequence in a cell
Available for: Tri 13/18/21, Prader-Willi, Angelman, Cri-du-chat, DiGeorge, Miller-Dieker, Williams, 4p deletion
What is mass spectroscopy and what is it used for?
Detection of very small differences in mass of PCR products because of variations in DNA sequence
Done prenatally or postnatally
What is a microarray and what is it used for?
Molecular fragments of DNA/protein attached to a glass or plastic slide in a specific order
Uses:
1. Comparative Genomic Hybridization (CHG) microarray: attempts to identify number of copies of a particular gene- determine loss/gain
2. Microarray expression analysis: determine over/under-expression
3. Mutation microarray analysis: identify mutations/polymorphisms
What is methylation analysis used for?
Detection of imprinting disorder.
Ex. Beckwith-Wiedemann syndrome
What is whole EXOME sequencing?
Determines nucleotide sequence of all protein coding sites (exomes)
*Useful if patient without a clear reason for specific phenotype
What is whole GENOME sequencing?
Sequences entire genome- introns and exons
Most common single-gene disorder in Caucasian population/life-shortening inherited disease
Cystic fibrosis
Autosomal recessive (nonsense mutation)
CFTR= cAMP regulated chloride channel, regulator of other Na/Cl channels
Characteristics of autosomal dominant disorders
- Each disease is rare in the population
- 1/200 people
- Wide variation of expression with vertical transmission
- NO SKIPPED GENERATIONS
- Male = Female (equally likely to transmit to offspring)
- Father to son transmission observed
- Recurrence risk: one carrier parents 50%, both parents affects 75%
Ex. spherocytosis, Waardenberg syndrome
Characteristics of autosomal recessive disorders
- RARE in population
- Less variation in expression
- Clustering of disease among siblings but not usually parents
- Male = Female (equally likely to transmit to offspring)
- Recurrence risk:
- 2 carrier parents 25%
- affected parent homozygous with unaffected parent= ALL offspring carriers
- affected parent homozygous with carrier 50%
- carrier parent mates with unaffected parent: NO offspring affects, 50% chance carrier
- 2x carrier parent: 25% affected, 50% carrier, 25% unaffected
- 2x affected parent: 100%
Ex. cystic fibrosis, majority of inborn errors of metabolism
What is the Lyon Hypothesis?
One X chromosome in each female cell is inactivated randomly early in embryonic development and cannot be reactivated–> becomes Barr body
Unequal # of X-linked genes in males/females
Females have 2 population of cells (X paternal, X maternal)
Males= no Barr bodies
Turners= no Barr bodies
Characteristics of X-linked recessive disorders
- Usually clinically evident in MALES
- SKIPS GENERATIONS
- Heterozygote female (phenotypically normal) = 50% transmitting DISEASE to son, 50% transmitting CARRIER to daughter
- AFFECTED father will transmit:
CARRIER to all daughters
CANNOT transmit disease/carrier to sons
ex. G6PD, Wiskott-Aldrich, hemophilia A/B
Characteristics of X-linked dominant disorders
- Rarer than X-linked recessive
- 2X Females > Males
- RARE to have skipped generations
- AFFECTED father: DISEASE to all daughters, CANNOT transmit to sons
- AFFECTED mother: 50% DISEASE to sons or daughters
Ex: In a family of 6, all girls have a disease but none of the boys do
Presents with:
- camptodactyly
- thick lips
- deep-set eyes
- prominent cupped ears
- deep creases in palms/soles
- mild to severe mental deficiency
- pelvic/hip dysplasia
Trisomy 8
Rare, mosaic
Complete Trisomy 8 usually lethal in utero
Presents with:
- Microdeletion from 15q 11-13 of MATERNAL origin (70%)
- inappropriate burst of laughter
- large mouth with protruding tongue
- blonde hair, decreased iris pigment
- initial hypotonia
- severe mental deficiency
- delayed motor skills
- ataxia and jerky movements
- seizures
Angelman
“Happy-puppet”
Describe Rubenstein-Taybi syndrome
16p13: cAMP-regulated enhance-binding protein (CREB)
Majority sporadic
- Cardiac (25%): PDA, VSD, ASD
- Broad thumbs and first toes, joint hyper mobility
- Downward slanting palpebral issues, hypoplastic maxilla, narrow palate, prominent/BEAKED nose
- Hirsutism, cryptorchidism
- Microcephaly
- Postnatal growth deficiency
- Increased risk of tumors- brain, leukemia
risk of developmental delay and mental retardation
Wilm’s tumor
Aniridia
GU abnormalities
Retardation
11p13 deletion
- prominent lips
- micrognathia
- malformed ears
- may develop gonadoblastoma
- short stature
- renal failure
How is achondroplasia inherited?
Autosomal dominant
80-90% from new mutations
Increase risk with increase paternal age
Physical characteristics of achondroplasia
- “trident” hands
- depressed nasal bridge
- megalocephaly
- short limps/stature
- caudal narrowing of spinal cord
- NORMAL intelligence
In-utero findings for Beckwith-Wiedemann
POLYHYDRAMNIOS, prematurity
Ear finding: linear earlobe fissures
Holt-Oram syndrome
Autosomal Dominant
Heart-hand syndrome
- ASD> VSD, Co-arct
- upper limb defects
- THUMB: absent, hypoplastic, abnormally shaped
- narrow shoulders
no correlation between severity of limb defect and cardiac defect
Direction of lens subluxation in Marfan’s
abnormal fibrillin gene at 15q21.1
AD
Usually UPWARDS
severe neonatal form can have lens dislocation
What other diagnoses must be considered when thinking about Noonan’s syndrome?
fetal hydantoin exposure
fetal alcohol syndrome
45,X/XY
What is the defect in osteogensis imperfecta?
Type I collagen
Describe the types of OI
There is significant overlap between all types especially II and III
- blue sclera, increased risk of fractures, deafness, Wormian bones in cranial sutures, easy bruisability
- WORST OUTCOME (stillborn or die early), dark blue sclera, dfractures, short and broad long bones, IUGR
- Blue sclera, fractures present at birth, IUGR, abnormal dentition, deafness
- normal to grey sclera, ? abnormal dentition
- Flat facies
- myopia
- spondyloepiphyseal dysplasia (flat vertebrae with anterior wedging, poorly developed distal tibial epiphyses, flat femoral epiphyses)
- mitral valve prolapse
- can be associated with Pierre Robin sequence
Stickler syndrome
Hereditary artho-ophthalmopathy when resulting from mutation of type II collagen
AD
Cloverleaf skull
“Telephone receiver” femurs
Platyspondyly (flat vertebral bodies)
Thanatophoric dysplasia
Cloverleaf specifically in Type II
Common characteristics of Treacher Collins
AD
lower eyelid coloboma
down-slantig palpebral fissures
mandibular hypoplasia
dysmorphic ears
malar hypoplasia
conductive hearing loss
vision loss
NORMAL intelligence
Dx: hypoplastic zygomatic arch on XR
Infant with white forelock and partial albinism
Deafness (defect in organ of Corti)
Lateral displacement of medial canthi (type I)
Synophrys
Waardenburg syndrome
What is the differential diagnosis for a cephalocele?
- Meckel-Gruber
- Amniotic band syndrome
- Frontonasal dysplasia
- Walker-Warburg syndrome
Describe TAR (thrombocytopenia-absent radii) syndrome
Autosomal recessive
Absent bilateral radii
THUMBS ALWAYS PRESENT
Ulnar abnormalities (+/- abnormal humerus)
Thrombocytopenia (~40% mortality hemorrhage in early infancy)
Cardiac abnormalities ~1/3
Fanconi Pancytopenia Syndrome
Inreased number of chromosomal breaks
AR
Radial hypoplasia
Thumb hypoplasia
Pancytopenia
Hyperpigmentation
Short stature
~35% mortality associated with hematologic abnormalities
Increased risk of AML
Congenital diaphragmatic hernia
Coarse facial features
Digital and nail hypoplasia
Fryns syndrome
What is the most common inherited cause of inherited mental deficiency?
Fragile X Syndrome
How did Fragile X get its name?
Finding of X chromosomes cultures in a low folic acid medium that may break near the tip of the long arm
Mutation in Fragile X
Triple repeat mutation
has >/= 60 CGG
methylated repeats = severity of expression
Physical features of Fragile X
long facies
prominent forehead
large ears
large testes post-puberty
mental deficiency
autism
hyperextensible fingers/joints
mild connetive tissue dysplasia
Infant presents with:
twisted, fractures light pigemented hair
progressive cerebral deterioration
seizures
Due to abnormality in copper transport = copper deficiency
Menkes syndrome
Kinky hair syndrome
X-linked recessive
Disorders associated with port-wine stains (nevus flammeus):
85% unilateral, head and neck
Beckwith-Weidemann
Cobb syndrome
Klippel-Trenaunay-Weber
Sturge-Weber
Infant with port wine stain, superficial vascular abnormalities, underlying hypertrophy of bones/soft tissues
Klippel-Treynaunay-Weber
Port wine stain with underlying spinal angiomas
cutaneomeningospinalangiomatosis
Cobb syndrome
Port wine stain with mental deficiency, seizures, hemiparesis contralateral to facial lesion, ipsilateral “tramline” intracortical calcifications
Sturge-Weber
Main features of Cat Eye Syndrome
extra part of Ch 22 in quad or triple at 22q11
Cardiac (33%)- TAPVR, persisten L SVC
down slanting palpebral fissures
anal atreasia
coloboma (hence cat-eye)
renal agensis
Infant with micromelia, synophyrs, thin down-turning upper lip, long and curly eyelashes, initial hypertonicity, microbrachycephaly, hirutism, low posterior hairline
Cornielia de Lange
Mutation in 1 of 3 cohesin-associated genes
NIPBL, SMC1L1, SMC3
Describe Mobius sequence
associated w/ limb reduction defects, Poland sequence, Klippel-Feil
6th and 7th nerve palsy
expressionless facies
micrognathia
talipes equinovarus
4 types of abnormal development:
1. destruction of central brain nuclei
2. hypoplasia or absence of central brain nuclei
3. peripheral nerve involvement
4. myopathy
Pierre Robin sequence
Secondary to mandibular hypoplasia prior to 9 weeks gestation
can be associated with Trisomy 18, Stickler syndrome, Treacher-Collins syndrome, fetal alcohol syndrome
micrognathia
glossoptosis
clef palate- U shaped
may require intubation for posterior airway obstruction
conductive hearing loss
tongue-lip adhesion/tracheotomy, mandibular distraction osteogenesis
Goldenhar syndrome
facio-auriculo-vertebral spectrum
oculo-auriculo-vertebral spectrum
Due to 1st and 2nd brachial arch abnormalities
VSD>PDA>TOF>Coarc
mouth abnormalities, ear pits/tags
tongue abnormalities
deafness
hemivertebra or hypoplasia of vertebrae (cervical MC)
70% unilateral (right>left) –> hemifacial microsomia
renal abnormalities
Characteristics of Klippel-Feil sequence
short neck
low posterior hairline
limited movement of head
abnormal cervical vertebrae
may have VSD, neurologic deficits, mental deficiency
Sequence associated with unilateral hypoplasia or absence of pectoralis muscle
ipsilateral UE abnormalites such as syndactyly
Poland sequence
possibly due to proximal subclavian arterial disruption in utero
Male>female, 75% right side
VACTERL
Diagnosis of exclusion, requires 3 of major abnormalities
Vertebral anomalies- 60-90%, scoliosis, tethererd spinal cord
Anorectal malformation- 55-90%, imperforate anus, anal atresia, fistula (GU abnormalites as well)
Cardiac- 40-80%, VSD>TOF, coarc, vascular anomalies
TE fistula- 50-80%, w or w/out esophageal atresia
Renal anomaly- 50-80%, renal agensis, cystic/dysplastic kidneys, horseshoe kidney, UPJ obstruction
Limb anomalies- 40-55%, upper>lower, raidal>ulnar
malformations of bones as a result of an insult during organogensis
dysostoses
result from abnormal organization of cells during early patterning events of skeletal development
skeletal dysplasia
results from mutated genes that are expressed in chondro-osseus tissue
primary skeletal dysplasia
results from abnormalities of extraosseus factors with secondary effects on the skeletal system
secondary skeletal dysplasia
What is PCR? How is the test performed?
polymerase chain reaction
amplifies a specific DNA sequenc from the genomic DNA by using two primers on either side of the sequence of interest
What is arthrogryposis?
Joint contractions
due to deformation
Where does cell-free DNA come from?
continuous turnover of villous trophoblast results in shedding of apoptotic material including cell-free DNA into the maternal circulation
Risk of another anomaly when talipes equinovarus
if diagnosed prenatally, 60%
if diagnosed antenatally, 10%
Expected finding on Tzank smear for incontinentia pigmenti
Eosinophils
Tzank smear shows multinucleated giant cells
Diagnosis
Herpes or varicella
Tzank smear shows neutrophils
Diagnosis?
Neonatal pustular melanosis
Infant with anosmia, low FSH and LH
Kallman syndrome
Low FSH/LH due to low HPA activity
Infant with optic nerve hypoplasia and absence of the septum pellucidum
Septo-optic dysplasia
Fetal condition most likley to pre-dispose to fetal heart rate abnormalities during labor
Potter syndrome
What nerve palsy often accompanies choanal atresia?
7th nerve palsy (cant close eye, cant open that side of the mouth)
choanal atresia also associated with lop ear anomalie
Genetic condition associated with congenital diaphragmatic hernia
Fryn’s syndrome
Rare, AR
digital and nail hypoplasia, coarse facies, cloudy cornea, anteverted nares
Most common mitochondrial disorder
Leigh Syndrome
lactate elevated in CSF/blood
Most common genetic condition associated with congenital heart defects
- Down Syndrome
- Noonan syndrome (pulm stenosis > cardiomyopathy)
Classic triad in Kartagener syndrome
situs inversus
bronchiectasis
chronic sinusitis
Pentalogy of Cantrell
- Omphalocele
- Defect of the lower sternum
- Defect in the pericardium
- Defect in the anterior diaphragm (diaphragmatic hernia associated with anterior foramen of Morgagni)
- Cardiac defect (coarctation)
Four clinical syndromes associated with hemizygous deletion of chr 22q11
- DiGeorge
- Velocardiofacial
- CHARGE
- CATCH 22
Diagnosis from FISH
Risk for recurrence from affected individual is 50% because AD inheritance pattern
Most common causes for severe mental retardation in the US:
- Downs syndrome
- FAS (MC preventable cause)
- Fragile X (MC inherited cause)
iodine deficiency- MC WORLDWIDE cause of preventable mental retardation
Most common modification in gene structure is:
Nucleotide variation- changes in single base pairs
Known as single nucleotide polymorphisms (SNPs)
Infant with broad thumbs and great toes, midface hypoplasia, and variable degrees of craniosynostosis (MC bicoronal)
Pfeiffer syndrome
Association of TAR and what allergy?
Cows milk protein
Eye finding in Alagille
posterior embryotoxin
Malformation
Morphological defect in an organ from an intrinsically abnormal developmental process
Something went wrong from the beginning
Due to genetic defect or teratogen
Can have a high recurrence risk
Deformation
Due to compression or distortion of an already normally formed body part
Recurrence risk is relatively low
Disruption
Breakdown or disruption of the originally normal developmental process, can look like a malformation
Recurrence risk is relatively low
Major anomaly
Congenital anomaly severe enough to need surgical intervention
increased morbidity and/or mortality
Potentially has a long term impact medically and/or psychologically
Minor anomaly
Congenital anomaly that requires no treatment at all or can be easily corrected
Do not cause increase morbidity or mortality
Often common in population
Noonan:
mutation
cardiac
PTPN11
PS
Alagille
eye: posterior embryotoxon
heart: PPS
mutation: JAG-1
Russell-Silver
AD
AR
XD
XR
triad of exocrine pancreatic insufficiency, skeletal abnormalities, bone marrow dysfunction (anemia, thrombocytopenia, leukopenia–> recurrent viral/bacterial infections)
Schwachman-Diamond
