Genetics - Peds Board Review

Front 1

Autosomal Dominant

Back 1

Vertical transmission of the disease phenotype, lack of skipped generations, and roughly equal numbers of affected males and females.
Recurrence risk is 50%.
Example: Postaxial polydactyly

Front 2

Autosomal Recessive

Back 2

Clustering of the disease phenotype among siblings, but not usually seen among parents or other ancestors. Equal numbers of affected males and females. Consanquinity may be presents.
Relative risk is 25%
Example: Albunism

Front 3

Incomplete (Reduced) Penetrance

Back 3

A person who has the disease-causing genotype might not exhibit the disease phenotype at all, even thought the disease-causing mutation can be trasmitted.
Example: Retinalblastoma - 10% of obligate carriers of the retinoblastoma-causing mutation (affected parent and affective children) do not have the disease.

Front 4

Variable Expression

Back 4

Degree of severity of the disease phenotype.
Maybe caused by environmental effects, modifier loci, or allelic heterogenity.
Example: Neurofibromatosis, type 1.

Front 5

Age Dependent Penetrance

Back 5

Delay in the onset of a genetic disease.
Example: Huntington Disease

Front 6

30 y/o woman had a sister who died from Tay-Sachs disease, an AR disorder that is fatal by age 6. What is the probability that this woman is a heterozygous carrier of the Tay-Sachs mutation

Back 6

2/3 heterzygous carrer
Remember, both parents had to be heterozygous carriers since they both lived past 6 years. She cannot be an affected homozygote because affected individuals die by age six, so either:
1. Disease allele from mother and normal allele from father
2. Disease allele from father and normal allele from mother, or
3. Normal allele from both parents.

Front 7

X-linked Recessive

Back 7

Absence of father-to-son transmission, skipped generations when genes are passed through female carriers, and a preponderance of affected males.
Example: Duchenne Muscular Dystrophy, Hemophilia A, Red-Green Colorblindness

Front 8

X-linked Dominant

Back 8

Absence of father-to-son transmission, skiiped generations are uncommon, twice as common in females as in males.
Example: Hypophosphatemic Rickets, Rett Syndrome (most males die in utero)

Front 9

Multifactorial Inheritance

Back 9

Many traits thought to be influenced by multiple genes as well as environmental factors.
Example: Height, Blood Pressure

Front 10

Mitochondrial Inheritance

Back 10

Mitochondria have their own DNA. Mitochondiral DNA is maternally inherited and has a high mutation rate.
Example: Leber Hereditary Optic Neuropathy (LHON) - missense, Myoclonic Epilepsy with ragged-red fibers (MERRF) - single base mutation, Kearns-Sayre disease - deletion/duplication.

Front 11

Prenatal Screening - Invasive

Back 11

Analysis of fetal tissue (amniocentesis, chorionic villus sampling, cordocentesis, and preimplantation genetic diagnosis)
- More cards in detail.

Front 12

Prenatal Screening - Noninvasive

Back 12

Visualization of the fetus
(Ultrasonography, MRI)
- More cards in detail.

Front 13

Amniocentesis

Back 13

- Performed at 15-17 weeks gestation.
- Withdrawl of amniotic fluid.
- Amniotic AFP is elevated with neural tube defects.
- Fetal loss is 1/200 above the background risk level.

Front 14

Indications for Amniocentesis

Back 14

- Maternal age > 35.
- Previous child with chromosomal abnormality.
- History of structural chromosome abnormality in one parent.
- Family history of genetic defect that is diagnosable by biochemical or DNA analysis.
- Increased risk of neural tube defect due to positive family history.

Front 15

Chorionic Villus Sampling

Back 15

- Performed at 10-11 weeks gestation.
- Provides diagnostic results in more than 99% of cases.
- Good for picking up inborn errors of metabolism.
- Confirmed placental mosaicism can confuse the diagnosis (mosaicism seen in placenta but not in the fetus - 1% to 2%)
- Fetal loss is 1% to 1.5%.

Front 16

Percutaneous Umbilical Blood Sampling (PUBS)
Cordocentesis

Back 16

Direct sampling of fetal blood and is used to obtain a sample for rapid cytogenetic or hematological analysis or for confirmation of mosaicism (from CVS).

Front 17

Prenatal Screening - Ultrasound

Back 17

Used to screen noninvasively for congential defects. Usually done around 18-20 weeks gestation.

Front 18

Maternal Serum AFP

Back 18

- Considered elevated wen 2 - 2.5 times higher than normal medial level for NTD
- Usually low levels for trisomy 21 and trisomy 18.
- Checked at 15-17 weeks post LMP

Front 19

Quadruple screen

Back 19

- Unconjugated estriol
- Human chodionic gonadotropin
- Inhibin-A
- AFP

Front 20

First-trimester screen

Back 20

- Useful for trisomy 21 in 80-85% of cases.
- Also trisomy 13 and 18.
- free B subunit of hCG
- Pregnancy-associated plasma protein A (PAPP-A)
- US of nuchal translucency

Front 21

Prenatal Screening - Preimplantation Genetic Diagnosis - Blastomere

Back 21

- Checking aneuploidy 3 days after fertilization in vitro.
- DNA amplification for single-gene diseases.
- Can lead to allele dropout, where one of the two alleles may be undetectable (heterozygote appears to be a homozygote).

Front 22

Prenatal Screening - Preimplantation Genetic Diagnosis - Blastocyst

Back 22

- Done at 100 cell blastocyst stage
- Takes from trophoectoderm of blastocyst, not the embryo.
- Avoids allele dropout.

Front 23

Prenatal Screening - Preimplantation Genetic Diagnosis - Polar Body

Back 23

- Examination of first or second polar body DNA.
- Useful when only the mother is at risk for transmitting a disease-causing mutation.

Front 24

Karyotype

Back 24

Ordered display of choromosomes.
Uses FISH
- Useful for detection of balanced translocation in developmental delay as part of an area could be cut of for transcription. (CGH will NOT pick this up).

Front 25

FISH

Back 25

Useful for detecting missing or additional chromosomal material and rearrangements.

Front 26

array Comparative Genomic Hybridization (aCGH)

Back 26

Differentially labeled DNA from test and control subjects is hybridized to metaphase in microarrays, allows the detection of deletions or duplications. Cannot identify balanced rearrangements.

Front 27

Newborn Screening

Back 27

Blood spot sent for genetic testing of multiple diseases that can cause morbidity and mortality and early diagnosis of chronic diseases.
Examples: PKU, Galactosemia, Congenital Hypothyroidism, CF

Front 28

Trisomy

Back 28

Three copies of a chromosome.

Front 29

Deletions

Back 29

Chromosomal break and subsequent loss of genetic material.

Front 30

Translocations

Back 30

Interchange of genetic materal between nonhomologous chormosomes.

Front 31

Duplications

Back 31

Unequal crossover during meiosis.
Less severe than deletions.

Front 32

Inversions

Back 32

Two breaks on a chromosome and reinsertions of the intervening fragment in inverted order.
ABCDEFG to ABEDCFG

Front 33

Contiguous Gene Syndromes

Back 33

Deletion of a series of adjacent genes
Example: WAGR syndrome (11p deletion).

Front 34

Turner Syndrome

Back 34

45 X
Proportionate short stature
Triangle-shaped face
Posteriorly rotated ears
Broad, "webbed neck"
Broad chest
Obstructive cardiac lesions (Bicuspid valve and Coarctation)

Front 35

Klinefelter Syndrome

Back 35

47, XXY
Taller than average (Longer limbs)
Small testes
Gynecomastia
Lower IQ scores

Front 36

47 XYY

Back 36

Taller than average
Reduced IQ
Higher than average male prison population (thought to be due to increase in behavioral disorders and learning disabilities).

Front 37

47 XXX

Back 37

Usually benign
Sterility, mestrual irregularity, or mild mental retardation.

Front 38

Pharmacogenetics

Back 38

Study of individual genetic variants that modify human responses to pharmacological agents.
Predict a person's response to drugs and reduce the incidence of drug-related side effects.

Front 39

Trinucleotide Expansion

Back 39

Increased number of repeats during meiosis or early fetal development that causes genetic disease.
Example: CAG repeat in Huntingtons

Front 40

Imprinting

Back 40

One allele from one parent is active, while the other allele is inactive. The silenced genes are said to be imprinted.

Front 41

Trisomy 21 - Incidence

Back 41

1/800 births
94% have extra chromosome 21

Front 42

Trisomy 21 - Presentation

Back 42

Hypotonia
Small ears
Brachydactyly
Up-slanted palpebral fisures
Epicanthal folds
Single tranverse crease
ASD, VSD
Duodenal atrsia/Hirschsprung

Front 43

Trisomy 21 - Complications

Back 43

Hypothyroidism
Atlantoaxial instability
Leukemia (ALL)
DM
Cataracts

Front 44

Trisomy 18 (Edwards) - Presentation

Back 44

Intrauterine growth retardation
High forehead
Microcephaly
Small face and mouth
Short sternum
Rocker botton feed
Clubfoot/clenched fist
Overlapping fingers
Structural heart defect

Front 45

Trisomy 13 (Patau) - Presentation

Back 45

*Think midline defects
Orofacial cleft
Postaxial polydactyly of the limbs
Holoprosencephaly
Hypoplastic or absent ribs
Genital anomalies
Heart malformations
Abd wall defects
Cutis aplasia

Front 46

4p- (Wolf-Hirschhorn Syndrome)

Back 46

Most common in girls
'Greek helmet' facies (ocular hypertelorism, prminent glabella, and frontal bossing)
Growth deficiency
Microcephaly
'Beaked' nose
Hypertension
Short philtrum
Hypotonia
Cardiac anomalies
Seizures

Front 47

5p- (Cri-Du-Chat Syndrome)

Back 47

'Cat's cry' changes in larynx
'Moon face' with telecanthus
Down-slanting palpebral fissures
Hypotonia
Short stature
Microcephaly
High-arched palate
Wide and flat nasal bridge
Mental retardation

Front 48

18q- (De Grouchy Syndrome)

Back 48

*Atretic or narrowed ear canals
'Frog-like' position with legs flexed, ext rotated in hyperabduction
Protuding mandible
Everted lower lip

Front 49

Angelman Syndrome - Maternall Derived 15q11-13

Back 49

Jerky ataxic movements
Characteristic gait
Hypotonia
Fair hair
Mid-face hypoplasia
Prognathism (large chin, mandible)
Seizures
Inapporpriate bouts of laughter
Severe mental retardation
Absent or severly delayed speech

Front 50

Prader-Willi Syndrome - Paternally Derived 15q11-13

Back 50

Severe hypotonia at birth
Obesity (after FTT at birth)
Short stature
Small hands and feet
Hypogonadism
Usually mild mental retardation

Front 51

7p11.23- (Williams Syndrome)

Back 51

Periorbital fullness with downturned, prominent lower lip
Friendly 'cocktail party' personality
Stellate pattern of the iris
Strabismus
Supravalvular aortic stenosis
Mental retardation
Hypercalcemia

Front 52

11p13- (WAGR Syndrome)

Back 52

Wilms tumor
Aniridia
Genitourniary anomalies
mental Retardation

Absence of 2 possible genes
- PAX6
- WT1 (Wilms tumor 1)

Front 53

20p12- (Alagille Syndrome)

Back 53

AD, Mutation in JAG1 gene

Bile duct paucity with cholestasis
Pulmonary valve stenosis and peripheral artery stenosis
Ocular defects
Skeletal defects - butterfly vertebrae
Triangular facies, pointed chin
Long nose with broad mid-nose

Front 54

22q11.2- (DiGeorge Syndrome)

Back 54

Cleft palate, velopharyngeal incomppetence (VPI)
Thymus agenesis or hypoplasia (immune deficiencies)
Parathyroid gland hypoplasia/agenesis (hypocalcemia)
Hypoplasia of the auricle and external auditory canal
Cardiac abnormalities (TOF>Aortic arch>VSD>TA)
Short stature
Behavioral problems

Defect of development of third and fourth phayngeal pouches

Front 55

Klinefelters Syndrome

Back 55

47, XXY

Tall with gynocomasita
Delayed 2nd sex development
Azoospermia, small testes

Front 56

Turners Syndrome

Back 56

45, X

Short stature
Ovarian failure/gonadal dysgenesis
Cardiac (Bicuspid aortic valve>coarctation)
Broad webbed neck
Posteriorly rotated ears
Lymphedema of the hands and feet
Cubitus valgus

Front 57

Cleft lip and/or cleft palate

Back 57

Sporatic, familial and herediatry causes
Fix lip within first 5 months
Fix palate 6-12 months

Front 58

Pierre-Robin Sequence

Back 58

Primary embryologic defect of mandibular hypoplasia
Displacement of tongue
Interrupted closure of the lateral palatine ridges
Cleft palate

Glossoptosis
Micrognathia
Respiratory distress
Feeding problems

Front 59

Amniotic Band Sequence

Back 59

Amniotic bands adhereing to any part of the fetal body

Disruptive clefts of face and palate
Constriction risngs of the limbs and/or digits
Amputations

Front 60

Hemifacial Microsomia

Back 60

Microtia/Anotia
Canal atresia
Perauricular tags

Cervical vertebral anomalies
Cardiac anomalies
Renal anomalies

Front 61

Goldenhar Syndrome

Back 61

Same as Hemifacial Microsomia + Epibulbar Dermoids

Microtia/Anotia
Canal atresia
Perauricular tags

Cervical vertebral anomalies
Cardiac anomalies
Renal anomalies

Front 62

Branchio-Oto-Renal Syndrome

Back 62

AD

Branchial cleft istulas/cysts
Perauricular pits
Cochlear/Stapes malformation
Mixed sensory and conductive hearing loss
Renal dysplasia
Pulm hypoplasia - rare

Front 63

Treacher-Collins Syndrome

Back 63

AD

Mandibular/Maxillary hypoplasia
Zygomatic arch clefts

Front 64

Achondroplasia

Back 64

AD with FGFR3 (most are de novo, increases with advancing PATERNAL age)

Disproportionately short stature with rhizomelic shortening
Trident hands
Macrocephaly
Flat nasa bridge, prominent forehead, and midfacial hypoplasia

Front 65

Achondroplasia - Complications

Back 65

Serous otitis media
Motor milestone delay
Bowing of legs
Foramen magnum stenosis and/or craniocervical junction abnormalities during infancy - compression of upper cord causing apnea, quariparesis, growth delay, and hydrocephalus.

Front 66

Thanatophoric Dysplasia

Back 66

Type I - bowed femurs
Type II - straight femurs, 'cloverleaf' skull

AD - FGFR3 (most are de novo) Most are lethal

Macrocephaly with short limbs
Xray shows platyspondyly (flatness of bodies of vertebrae) flared metaphyses and short iliac bones

Front 67

Osteogenesis Imperfecta - General

Back 67

Osseous fragility
Short stature
Skeletal findings of variability

*None cause retinal hemorrhage or subdural hematomas - Think NAT

Front 68

Osteogenesis Imperfecta - Type I

Back 68

Mildest and most common form

Blue sclera
Delayed fontanelle closure
Hyperextensible joints
Hearing loss
Stature near normal
Multiple fractures (most occur prior to puberty)
*Fractures rarely occur at birth*
Scoliosis and hearing loss by age 20-30

Front 69

Osteogenesis Imperfecta - Type II

Back 69

Most severe form
Death in newborn period due to respiratory insufficiency
Numerous fractures and severe bone deformity

De novo AD mutation of COLIA1

Front 70

Osteogenesis Imperfecta - Type III

Back 70

Point mutation COLIA1

Numerous fractures in newborn
Short stature
Blue sclera at birth which lighten over time
Hydrocephalus and basilar skull invagination (complications)

Front 71

Osteogenesis Imperfecta - Type IV

Back 71

Point mutation in COLIA2
(Like Type I)

Sclerae white
Fontanelle closure delay
*Tibial bowing*

Front 72

Marfan Syndrome - General

Back 72

AD
Affects eyes, circulatory, skeleton, skin, lung and dura
Deaths due to Aortic Root dilation and rupture

*Look for 'high arched palate, dislocated lens, pectus carinatum/excavatum, and mitral valve prolapse'

Front 73

Marfan Syndrome - Diagnosis (2010 Ghent Criteria)

Back 73

WITHOUT Family History
1. AO and EL
2. AO and FBN1 gene
3. AO and systemic score 7 or higher
4. EL and FBN1 gene with known AO

AO = aortic diameter Z score 2 or more
EL = Ectopia Lentis

WITH family history
5. EL and FH
6. Systemic score 7 or more and FH
7. AO and FH

FH = Family History

Front 74

Ehlers-Danlos Syndrome

Back 74

AD connective tissue disorders

Hyperextensible skin
Hypermobile joints
Easy bruising
Dystrophic scarring
Skin - extra, fragile, abnormal scarring, wrinkled palms and soles
Cardiac - MVP and Proximal aortic dilatation