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.............................................."An International Alliance of Support and Science"

PMSF International Family, Research Conference


July 20-23, 2016, in Orlando, Fla.


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April is Autism Awareness Month


Q&A: EU-AIMS leader talks about autism, finding the elusive SHANK3 mutation and whether PMS cases are common


Dr. Thomas Bourgeron is one of the world’s foremost experts in the genetics of neuropsychiatric conditions, especially autism. He works at the Pasteur Institute in Paris and is a leader in EU-AIMS, a European autism research consortium in which SHANK3 – the cause of the majority of Phelan-McDermid Syndrome cases -- is an area of focus. April is Autism Awareness Month and PMSF Research Support Committee Chair Geraldine Bliss talked with Dr. Bourgeron about PMS, SHANK3 and autism.


BLISS: You recently led a team of thirty-seven researchers from around the world in a project where you looked for deletions and mutations of the genes SHANK1, 2 and 3. You compiled data from 14 published datasets and found that deletions and truncating mutations of SHANK3 occurred in 0.69 percent of people with autism.  When you looked at individuals who have both autism and intellectual disability, the rate is even higher, 2.12 percent.  (A truncating mutation is genetic spelling error that prevents the proper expression of the normal protein product.)

How do those figures compare to previous estimates about the rate of SHANK3 deletions and mutations in people with autism and developmental disability?

BOURGERON: This collaborative study is the first meta-analysis of SHANK mutations in ASD (Leblond et al. PLOS genetics 2014). There was especially a need to gather results of sequencing studies. A second objective of our study was to provide a clinical characterization of patients carrying SHANK mutations.


BLISS: What is the reason for the increase in the estimates of SHANK3 deletions and mutations from past estimates?

BOURGERON: We can divide SHANK3 genetic alterations in three types: First, large deletions encompassing SHANK3 (also known as 22q13 or 22qter deletions) are screened by standard karyotypes (a method to observe the chromosomes of one individual). Second, small deletions of SHANK3 (also known as copy number variants (CNV)) are well screened using DNA arrays (a method to identify small loss or gain of DNA). Finally, point mutations affecting a single nucleotide (letter) of the SHANK3 gene are much less studied since you need to use either classical Sanger or next generation sequencing methods.

In our study, we have increased the number of patients and controls screened for SHANK mutations (especially, we screened a new cohort of patients for SHANK3 point mutations by Sanger sequencing). This is one of the two reasons why the prevalence of SHANK3 mutations has raised. The second reason is that we have extended the screening of patients with autism and intellectual disability. Given that mutations of SHANK3 are found more often in patients with intellectual disability, we could detect more mutations than reported in previous studies.


BLISS: How does that rate compare to other genetic causes of autism and developmental disability?

BOURGERON: The group of Evan Eichler has recently published a map of genes associated with developmental disorders (Coe et al. Nat Genet 2014). The map is based on the analysis of 29,085 patients with developmental disorders and 19,584 controls. In this map, SHANK3 is the third locus associated with developmental disorders with a prevalence of the deletion in 0.5 percent of the patients. SHANK3 is one of the main genes associated with developmental disorders.


BLISS: The PMS community includes many individuals with deletions of 22q13 that span SHANK3 and a growing number of individuals with mutations of SHANK3.  Mutations of SHANK3 continue to be difficult to identify.  What are the challenges in sequencing SHANK3?

BOURGERON: There are unfortunately many challenges in sequencing SHANK3. First, the gene contains more than 22 exons (different fragments of the gene that you have to study individually). Second, the gene is extremely rich in nucleotides G and C. This feature increases the difficulty to sequence the DNA (even the exome sequencing strategy was not able to sequence some exons). Third, there were several mistakes in the SHANK3 sequence of the referenced human genome.

The good news is that we have corrected the sequences (the corrections are listed in Leblond et al. PLOS genetics 2014) and the new whole genome sequence methodologies greatly improve the screening of SHANK3 exons.


BLISS: Recently I’ve been hearing about new, very large sequencing studies.  Do you think the rates of SHANK3 deletions and mutations are likely to increase in larger studies?

BOURGERON: Unfortunately, the whole exome sequencing (a technology that enable the sequence of the coding regions of the genome) has difficulties to identify SHANK3 mutations (the same is true for SHANK1, less for SHANK2). The whole genome sequencing technology is much better, but still expensive (>$1,000 per genome). We are however confident that the price will drop soon.


BLISS: When you totaled up the data from the fourteen published datasets, you found that the prevalence of SHANK3 deletions in people with autism was 0.18 percent and the prevalence of SHANK3 truncating mutations was 0.51 percent.  I was surprised to see that mutations of SHANK3 occurred more than twice as often as deletions of SHANK3.  Could that have been a result of other factors in the studies (such as how they developed heir cohorts, perhaps including patients with autism but excluding patients with ID)?

BOURGERON: The IQ of the patients can greatly bias the results. This is why we have stratified the population for presence (IQ70) of intellectual disability.


BLISS: I was also surprised to see that in a cohort of patients with autism that you screened, 8 of 429 (1.86 percent) had truncating mutations of SHANK3. This is more than three times the rate the meta-analysis would have predicted.  What explains the very high yield of SHANK3 mutations in your cohort?

BOURGERON: The mean IQ of our cohort is lower than other cohorts, such as the Simon Simplex Collection (SSC). This is the main reason why our prevalence of SHANK3 mutations is higher. When IQ is taken into account, there was no difference between cohorts.


BLISS: What do your new findings mean for clinicians when they see patients with autism or developmental disability?

BOURGERON: Given the relatively high prevalence of SHANK3 mutations, we have suggested that SHANK3 should be routinely tested for patients with ASD and intellectual disability. As explained above, the screen for SHANK3 mutation remains difficult to perform, but hopefully the screening will be easier in the very near future.


BLISS: In the United States, we don’t have any surveillance programs for PMS or other rare neurodevelopmental disorders.  Do you care to wager a guess about the actual number of people who have deletions and mutations of SHANK3?

BOURGERON: This is an important question and unfortunately I have no precise answer on the number of patients with SHANK mutation. Based the current estimates, I would say that the prevalence of SHANK3 mutations is 1/10,000-20,000 births. This is less than Fragile X (1/4,000 males), but similar to Rett syndrome (1/10,000 females).


BLISS: Thank you for talking to us about your work. We wish you continued success.


3 main objectives of Dr. Bourgeron’s group


(1) Dr. Anne Claude Tabet aims at identifying all the patients with deletions or duplications including SHANK3 in France. We have already identified 50 patients with 22q13 deletions. This work is done in collaboration with all the cytogeneticists from France and should be completed this year. We will also extend this study to other European countries as we are currently doing so with the EU-AIMS project.


(2) Dr. Roberto Toro aims to identify modifier genes that influence the severity of SHANK3 mutations. As you know, some patients have difficulty walking and some go to school and can talk. We suspect that the genetic background of each individual will greatly influence the severity of the clinical outcomes. Because the genetic background is made of a large number of variants (>1,000 or maybe > 10,000 variants), we need to have genetic data on a very large population of patients carrying SHANK3 mutations. The PMS association will be very helpful for this project.


(3) Dr. Richard Delorme aims to initiate new clinical trials in patients carrying SHANK3 mutations. To identify new pharmacological treatments, Dr. Isabelle Cloëz-Tayarani, in collaboration with Alexandra Benchoua at iStem and Tobias Boeckers at Ulm university, is studying neurons derived from induced pluripotent stem cells (iPSC) of patients carrying a SHANK3 mutation. Dr. Elodie Ey is studying the social communication of mice mutated for SHANK2 or SHANK3. Using these cellular and animal models, we are currently testing the effect of new candidate molecules. If these tests are positive, Dr. Richard Delorme will start the clinical trials.

 


 

 


WATCH NOW: Mom hopes to raise awareness about rare genetic disorder

on St. Patrick's Day. Story, video via WDEL 1150 AM


Families come through again, everyone is PHELAN LUCKY


By Jennifer Randolph

Mother to Jack


I can’t say that I wasn’t nervous about following last year’s PHELAN LUCKY campaign; it was surprisingly popular.  This year, I felt like the pressure was on!

 

I was nervous that people who bought T-shirts the year before would not buy again and subsequently limit sales.  I was so wrong!

 

Our PMSF family rose to an incredible challenge and did so in such an amazing way.  PHELAN LUCKY 2015 t-shirts went on sale Feb. 4-21.  In seventeen days, we sold 956 T-shirts (compared to last year’s 488) and raised $16,240, plus additional money that was sent directly to the foundation. Over the two years of sales, more than $27,000 was raised for the Foundation.

 

At least one shirt (more in many cases) made it to each of the 50 states and five other countries.  Wyoming gave us the most problems but that was easily fixed by sending a PHELAN LUCKY shirt to Gov. Matt Mead! I bet he will be PHELAN LUCKY when his mail comes in early March.

 

“Jennifer Randolph has set a stellar example of how a single person can grow from a passionate rare disease parent and donor into a world-class, semi-professional fundraiser for organizations such as the Phelan-McDermid Syndrome Foundation,” said Andrew Moss, president of Booster, LLC. “We’re honored and happy to see the exceptional results she achieved in leveraging the goodwill and generosity of the PMS community to spread the word and to build widespread support for the PMS Foundation and its great work!”

 

Through Booster T-shirt crowdfunding for causes, individuals and groups design a custom cause-branded shirt (or other merchandise items), put them up for sale on a dedicated campaign webpage, and then raise money when supporters buy shirts and make donations. Shirts also act as “walking billboards,” promoting the cause.

 

When I looked at the leaderboard and reading some of the things that family, friends and even strangers wrote was so incredibly touching. We all know that raising a child with PMS is not easy, most of the time it is the hardest thing in the world.

 

That being said, we have a shared goal, the betterment of our most precious gifts, our children.  This is why I believe PHELAN LUCKY was so successful this year. Thank you to everyone who bought a shirt, shared a link, emailed Ellen DeGeneres (we’ll get her next year), watched the video and cheered us on during the last couple of hours! When we work together, great things happen.

 

While PHELAN LUCKY 2015 has officially closed, I still need your participation. Please send to me at This e-mail address is being protected from spambots. You need JavaScript enabled to view it pictures of you in your PHELAN LUCKY T-shirts in creative places. Let me know where you are and why you are PHELAN LUCKY. Reach out to all of your supporters and ask them to do the same. I would love to create a better video for next year (although I thought this year’s wasn’t half bad)! We need to raise awareness and viral videos are known to do that.

 

Enjoy your St. Patrick’s Day and keep PHELAN LUCKY, we have a lot to be thankful for!

 


 

 

 

PMSF part of rare disease consortium

 

The Phelan-McDermid Syndrome Foundation is delighted to announce PMS is one of the diseases included in the new “Developmental Synaptopathies Consortium” through the Rare Disease Clinical Research Network (RDCRN).  This consortium includes PMS and two related disorders – Tuberous Sclerosis Complex and autism-associated PTEN mutations.


What does it mean for us?  We will have Seaver Autism Center (NYC), NIH (Bethesda, Md.), Rush Memorial (Chicago) and Boston Children’s working together to collect clinical data from our children.  Each site will follow a common protocol and will share participant data with each other – both of which are especially important in accelerating rare disease research.


Enrollment is expected to begin in the spring of 2015. PMSF will keep you informed about RDCRN-related activities and about when recruitment for the studies will begin.


Read more here:

NIH: http://www.nih.gov/news/health/oct2014/ncats-08.htm

Boston Children’s: http://www.prnewswire.com/news-releases/boston-childrens-hospital-to-lead-nih-funded-rare-diseases-consortium-studying-autism-and-intellectual-disability-278525561.html





Foundation unveils new logo that represents

our worldwide communities of influence

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NEW! Mark your calendar

 

Make a note of these significant upcoming events.

 

Month of April Autism Awareness Month. Light It Up Blue to show your support for research, awareness and those with autism.

 

April 17-18 Region 12 Scientific days featuring PMS at Francisco de Vitoria University in Madrid. Doctors from U.S., France and Spain will be involved.

 

April 26 Region 6 The London Marathon

 

May 1 Become a member of the PMS Foundation. Go to www.pmsf.org and click on Membership menu link.

 

May 4 PMSF Board of Directors conference call

 

May 9, 10 PMSF France gathering

 

May 9 Unique Regional Family Day, Devon and Cornwall, Exeter Racecourse

 

May 10 Mother's Day

 

May 15 PMSF Global Partners meeting, London

 

May 15-17 Region 9 Family Gathering, Ludlow Falls, Ohio

 

May 16 PMSF United Kingdom gathering, London

 

May 16 Region 6 Family Day

 

May 17 Region 4 South Genetic Disease Table / Gathering, Brandywine Zoo, Wilmington, Delaware

 

May 18, 19 PMSF Italian gathering, Milan

 

May 22-24 PMSF Spanish gathering, Madrid

 

May 25 Memorial Day

 

June 1 PMSF Board of Directors conference call

 

June 7-13 Chromosome Disorder Awareness, sponsored by Unique rarechromo.org

 

June 15 Did you update your profile in the PMS International Registry? Do it before summer arrives.

 

June 23 Father's Day

 

July 4 Independence Day in United States

 

July 6 PMSF Board of Directors conference call

 

Aug. 3 PMSF Board of Directors conference call

 

Aug. 22 Region 9 Logan’s Heroes Motorcycle Ride and Auction fundraiser, Davison, Mich.

 

Sept. 1-2 Giving Challenge

 

Sept. 27-29 140th Annual Meeting of The American Neurological Association, Chicago

 

July 20-23, 2016 PMSF International Conference, Caribe Royale Hotel and Conference Center, Orlando, Florida


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