Download Dr. Stephanie Sherman Fragile X Research

DR. STEPHANIE SHERMAN
FRAGILE X SYNDROME
Wei Wei Chen
CS 153 | Prof. Michelangelo Grigni | Fall 2016
QUICK OVERVIEW
INTRO
FRAGILE
X
RESEARCH:
LEARN
RESEARCH:
INFORM
GET
INVOLVED
Q&A
WHO IS DR. SHERMAN?
P RO F E S S I O N
E D U C AT I O N
• Emory Professor
• PhD, Human Genetics,
Indiana University Medical
School
• Human Genetics
department
• Board Certified Medical
Geneticist
• BS, North Carolina State
University
A R E A S O F S P E C I A L I Z AT I O N
• Genetic causes of intellectual and
developmental disorders
• Nondisjunction of human
chromosomes
• Primary ovarian insufficiency
• Genetic mapping of complex traits
• Fragile X syndrome
• Down syndrome
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
WHAT IS FRAGILE X SYNDROME?
• Fragile X syndrome is a genetic condition
that is caused by a break or weakness on
the long arm of the X chromosome
• It leads to intellectual disability,
behavioral and learning challenges and
various physical characteristics
• Usually no life-threatening health
concerns associated with the condition
https://fragilex.org/fragile-x/fragile-x-syndrome/
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
FRAGILE X CHARACTERISTICS: MALES
• Behavioral: ADD, ADHD, autism and autistic
behaviors, social anxiety, hand-biting and/or flapping,
poor eye contact, sensory disorders and increased
risk for aggression
• Physical: large ears, long face, soft skin and large
testicles (called “macroorchidism”) in post-pubertal
males
• They are also very social and friendly, have excellent
imitation skills, have a strong visual memory/long
term memory, like to help others, are nice, thoughtful
people and have a wonderful sense of humor
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
https://fragilex.org/fragile-x/fragile-x-syndrome/
GET INVOLVED
Q&A
FRAGILE X CHARACTERISTICS: FEMALES
• Characteristics seen in males also
seen in females (milder)
• Only ~1/2 of all females who
carry the genetic mutation have
symptoms
• Of those, ½ are of normal
intelligence and only ¼ have an
IQ under 70
https://fragilex.org/fragile-x/fragile-x-syndrome/
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
THE FRAGILE X (FMR1) GENE
• FMR1 – fragile x mental retardation
• Location on chromosome: Xq27.3
• Everyone has the FMR1 gene – Fragile X
syndrome is a mutation of the gene
• Fragile X syndrome is caused because
people with the disease don’t make a
particular protein, FMRP
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
DIFFERENT KINDS OF FMR1 MUTATIONS
• Mutation of FMR1 gene involves a repeating pattern of DNA called a
“CCG” repeat
• In FMR1 gene, there is an area of the promotor that is rich in these
repeats and is measured when fragile X testing is performed
NORMAL
P R E M U TAT I O N
F U L L M U TAT I O N
• <54 repeats
• ~55-200 repeats
• >200 repeats
• Gene turned off - methylation
https://fragilex.org/fragile-x/genetics-and-inheritance/fmr1-gene/
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
Normal
Premutation
Full mutation
(<54 repeats)
(55-200 repeats)
(<200 repeats)
DNA
Transcription
mRNA
Translation
protein
(FMRP)
RNA-binding protein that
regulates translation
Diagram courtesy of Patricia Jacobs
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
WHAT WAS / IS DR. SHERMAN’S
RESEARCH?
• GOAL 1: To understand the environmental and genetic factors that
increase the risk and severity of both FXPOI and FXTAS.
• GOAL 2: In collaboration with Dr. Jeannie Visootsak, the clinical
director of the Emory Fragile X Center, work to translate findings to
families with fragile X associated disorders
http://genetics.emory.edu/faculty/primary/sherman-stephanie.html
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
GOAL 1
• GOAL 1: To understand the environmental and genetic
factors that increase the risk and severity of both FXPOI and
FXTAS.
• GOAL 2: In collaboration with Dr. Jeannie Visootsak, the clinical
director of the Emory Fragile X Center, work to translate findings to
families with fragile X associated disorders
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
FXTAS / FXPOI
• FXTAS (Fragile X-associated Tremor/Ataxia Syndrome)
• Symptoms can include: tremor > ataxia (loss of coordination of
the muscles) > dementia
• FXPOI (Fragile X-associated Primary Ovarian Insufficiency)
• Symptoms can include: irregular periods/menstrual cycles, infertility, early
menopause (before age 40)
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
PREMUTATION
FXTAS
DANGERS:
/ FXPOI
FXPOI / FXTAS
• FXTAS (Fragile X-associated Tremor/Ataxia Syndrome)
• Symptoms can include: tremor > ataxia (loss of coordination of the muscles)
> dementia
• FXPOI (Fragile X-associated Primary Ovarian Insufficiency)
• Symptoms can include: irregular periods/menstrual cycles,
infertility, early menopause (before age 40)
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
FXTAS/FXPOI PREMUTATION PROJECT
• “We have established a large genetic epidemiological study of nonclinically referred individuals with high repeat tracts to study the
neurological and neuropsychological consequence of these alleles.”
• “For females, we also study hormone levels and reproductive histories
to better understand factors related to the risk of POI.”
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
CURRENT LAB WORK AT EMORY
• Field Group gets samples
• Lab Group sets up samples to be sent to
HudsonAlpha Institute for Biotechnology in
Huntsville, AL
• Dr. Sherman and team (Dr. David Cutler) analyze the
sequencing data that comes back from HudsonAlpha
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
GOAL 2
• GOAL 1: To understand the environmental and genetic factors that
increase the risk and severity of both FXPOI and FXTAS.
• GOAL 2: In collaboration with Dr. Jeannie Visootsak, the
clinical director of the Emory Fragile X Center, work to
translate findings to families with fragile X associated
disorders
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
HOW IS FRAGILE X INHERITED?
• Since the gene is carried on the X chromosome, both males and
females can pass on the gene
• A father can only pass the gene on to his daughters
• Even if he has the full mutation, the daughters will only receive the
premutation gene
• A mother can pass the carrier and full mutation gene to sons and
daughters
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
FRAGILE X PEDIGREE EXAMPLE
60, 30
XX
XY
83
72, 29
XX
XY
>200
XY
XY
XX
90, 31
XX
XY
XY
>200
XX
79, 30
XX
XY
>200
XY
>200
XX
>200, 30
89, 30
XY
XX
ANTICIPATION AS A BIOLOGICAL
PHENOMENON
• Anticipation means the increased severity and earlier age at onset of a
particular disease, or the increased risk for that disease, with every
new generation (L. Penrose, 1948)
Advances in Bioscience & Clinical Medicine (S.Peric)
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
WHAT PROBLEM IS STUDIED?
• Dr. Sherman and team try to ask the question: Can we improve that
risk? Knowing the repeat size, can we counsel women / families better
if they are at risk for having child with Fragile X.
• Not all repeats are pure CGG repeats
(CGG)9, AGG, (CGG)9, AGG, (CGG)40 vs (CGG)60
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
HOW CAN YOU GET INVOLVED?
• Understand how to coil through big datasets, how to identify the
important parts to prioritize variant (bioinformatics)
• Knowing biology and big data science is important
• Understanding Population Genetics (Dave Cutler is trained in this; then
picked up all the computer stuff around that) helps you determine how
often you should see a variant, whether or not what you’re seeing is an
error or the norm, etc.
• Cross-training in computational and biological side will help
understand data better
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
CONTACTS
• Stephanie Sherman | [email protected]
• David Cutler | [email protected]
• Jeannie Visootsak | (404) 778-8500
• Fragile X Syndrome Clinic: http://genetics.emory.edu/patientcare/fragile-x.html
INTRO
FRAGILE X
RESEARCH: LEARN
RESEARCH: INFORM
GET INVOLVED
Q&A
QUESTIONS?