10/29 Variation In Expressivity*

Front 1

dysmorphology

dysmorphic

Back 1

the study of birth defects in children

when you have morphologic developmental abnormalities

Front 2

syndrome

Back 2

characteristic and recognizable pattern of multiple congenital anomalies usually causally related

Front 3

penetrance
What type(s) of mutation typically involved?

Back 3

All-or-nothing phenomenon for expressing a mutant gene.
Usually talking about autosomal dominant (x link works too)

Front 4

Example of variable expressivity.
What is it?
What type of mutation typically shows varying expressivity?

Back 4

Polydactyly. Sister only had bump on hand.

Degree to which a gene expresses itself in an individual.

Usually in autosomal dominant

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pleitropy

Back 5

single gene (AD) or gene pair (AR) has effects on several organ systems

Front 6

Example of pleitropy
What gene makes this example?
What protein does it make?
What does that protein do?

Back 6

Marfan syndrome
FBN1 (really big)
Fibrillin gene
Fibrillin is a major component of connective tissue collagen

Front 7

Marfan syndrome penetrance?
Expressivity?

Back 7

100% penetrant.
Variable expressivity: unclear why

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Marfan syndrome inheritance pattern?
What % are new mutations?

Back 8

autosomal dominant
50%

Front 9

What systems do Marfan syndrome affect? 5

What are major features you see? 11

Back 9

cardiovascular, skin, ocular, pulmonary, skeletal

tall (compared to family),
thin (dolichostenomelia),
arachnodactyly,
myopia (significant),
ectopia lentis (dislocated lenses)*,
mitral valve prolapse,
aortic root dilatation,
pectus excavatum funnel chest,
pectus carinatum pigeon breast,
ratio of Lower Segment to US: LS >> US.
arm span>height

Front 10

What makes ectopia lentis a good marker for Marfan syndrome?

Back 10

Really rare in general population, but very common in Marfan pts

(pts usually have poor vision)

Front 11

Minor features of Marfan syndrome 5

Back 11

striae (stretch marks) (surprising in thin young people)
triangle face
joint hypermobility
hernias
pes planus (flat feet)

Front 12

NF type 1: full name
Misconception?

Back 12

Neurofibromatosis type 1
-not elephant man-
mutation in a the very large gene

Front 13

NF-1 incidence rate and population

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1 in 3-4000. 100k people in the US

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NF-1 inheritance pattern

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autosomal dominant

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What does NF-1 code for?

Back 15

Makes neurofibromin which is a tumor suppressor

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NF-1: What are 3 typical manifestations on skin?

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cafe-au-lait spots. uniformly light brown macules with defined borders. you see multiple.

freckling in axillary and/or inguinal. Areas not usually sun exposed

subcutaneous neurofibromas: benign tumors of fibrous tissue and proliferation of Schwann cells. can vary in size, number, location.

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NF-1 eye manifestations

Explain subset type

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Lisch nodules (iris hamartomas: benign tumor [neoplasm], grows at same rate as surrounding tissue but disorganized). Sometimes grossly visible as brown on grey eyes

optic gliomas: tumors on optic nerves. makes them protrude.

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NF-1 other manifestations 8

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Pseudarthrosis: get fractures and they don't heal. Deossification of weight-bearing long bone (tibia and fibula). Makes it curved and more prone to future fractures.
scoliosis
short stature
limb length discrepancy
seizures
macrocephaly
sensorineural deafness
learning/IQ problems

Front 19

Minimum diagnostic criteria for NF-1

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2 or more of:
6 cafe-au-lait spots
two+ neurofibromas
freckling in axillary/inguinal areas
optic glioma
two+ lisch nodules
distinctive osseous lesion
first degree relative with NF-1

Front 20

NF-2
4 signs

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"Central NF"
Tumors of CNVIII making sensorineural deafness
Meningiomas of brain/schwannomas of spinal cord
Can have the 3 skin manifestations of NF-1
Juvenile posterior subcapsular lenticular opacities (cataracts)

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Theory of how autosomal dominant has varied expressivity

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maybe wt gene compensates/affects

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How you get the same phenotype via different mechanisms or genetic etiologies (2)

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locus heterogeneity: mutations at two or more different loci

allelic heterogeneity: different mutations in the same gene

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Ehlers-Danlos syndrome

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connective tissue disorder (collagen)
Has many different forms of different severities, but all same features.
Locus heterogeneity example

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symptoms of Ehlers-Danlos: 4 expected, 6 variable

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hyperelastic velvet skin
bruise easy/poor wound healing
hyperextendible joint
blue sclarae
variable: rupture eye (showed picture), deafness, vascular fragility, scoliosis, hernias, joint dislocations

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our famous example of allelic heterogeneity and some basic info

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Cystic fibrosis. AR. CFTR. 1000 different versions. deltaF508. chromosome 7.

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Prader-Willi syndrome and Angelman syndrom illustrate ____________

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genomic imprinting and uniparental disomy

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Prader-Willi syndrome at
birth?
3-4 years of age?

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delayed milestones and mentally
at birth:
hypotonic (poor muscle tone, floppy; down syndrome has this too though)
do not feed well because of muscle lacking
failure to thrive (not feeding or growing well)

3-4 years age: starts to feed/grow (false relief for parents). Driven to eat as much as they can.
almond shaped eyes. small hands and feet. Don't use calories. Don't throw up. folds on eyes Asian look. small penis/small scrotum. pick at skin.

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Angelman Syndrome: 7.5

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small growth.
microcephaly.
closely spaced eyes.
mouth appears large.
mental retardation- poor/no speech.
have seizures in second phase 3-4 years.
outbursts of laughter. (esp tuning forks).

Front 29

Comparing mutation inheritance in Prader-Willi and Angelman

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in Prader-Willi 3/4 have deletion on chromosome 15 from father (didn't use mother's). Angelman syndrome 3/4 had same deletion on chromosome 15 from Mother (didn't use father's).

The other 1/4 of each had disomy of 15, still not using the same respective parent's chromosome
(PW 2 15's from maternal;
Angelman had 2 15's from paternal).

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uniparental disomy

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2 homologous chromosomes from same parent.

so Prader-Will 2 maternal 15s
Angelman syndrome 2 paternal 15's

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genomic imprinting

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variable expression of genetic material depending on maternal/paternal derivation- in a small subset genes are turned off in a parent-of-origin manner (epigenetically marked or imprinted (usually methyls) in the sperm/egg)-- why you don't use the good copies in UPD

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microdeletion syndrome

example

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contiguous gene syndrome
usually mutation is just one gene. but a big one can be several. or 2. or 10.

22q11 deletion varies and people had different effects and then they realized it was the same situation of just different deletion types

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FISH analysis

example tags

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florescent in situ hybridization. glowing probes attach to small regions and you can see microdeletions, origins of extra material, translocation origins

tuple 1 and ARSA

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Define mosaicism

two types of mosaicism

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individual from single zygote have 2 cell lines in differing genotype/karyotype

somatic mosaicism - milder. passed on to fewer cells
germline mosaicism: two cell lines in germ cells- difficult to counsel because parent somatic cells not carriers/affected