Search our Site. Find Results Fast.

In Loving Memory Melissa passed away from complications after a stem cell transplant, necessitated by Shwachman-Diamond Syndrome. Her mother Sherry created a Facebook page (Swab4Melissa SDS Cancer Awareness) in her memory to advocate for various cancer awareness campaigns and to spread positivity through their #WeChoseJoyTogether campaign, which includes a balloon initiative inviting anyone in the community to bring smiley face Mylar balloons to their local children's hospital. Sherry shared her story in the context of grief through a beautiful video for the Stories of Hope series by the New Hope Grief Support Community. Thank you for sharing Melissa's and your family's story, Sherry.

In this issue: New study reports the economic impact of a delayed diagnosis is up to $517,000 in avoidable costs per patient in rare diseases Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! Groundbreaking Study Reveals Staggering Economic Toll of Delayed Rare Disease Diagnosis: Report Calls for Urgent Advancements in Policies and Technologies In our Science Snapshot earlier this month, we discussed the diagnostic odyssey many individuals with Shwachman-Diamond Syndrome experience. Because these long diagnostic journeys are not uncommon across rare disease, there are organizations such as The EveryLife Foundation for Rare Diseases (and SDS Alliance!) who are committed to performing and funding research crucial to shortening this time to receive a diagnosis. In September, the EveryLife Foundation released one of the first studies of healthcare resource utilization and costs for patients with rare disease. The Cost of Delayed Diagnosis in Rare Disease: A Health Economic Study is a landmark report showing the cost savings of receiving a more timely diagnosis in rare disease. This study was performed as a follow-up to the National Economic Burden of Rare Disease Study and provides an in-depth analysis of the avoidable costs associated with seven rare diseases: Adrenoleukodystrophy (ALD), Duchenne muscular dystrophy (DMD), Fragile X syndrome (FXS), Generalized myasthenia gravis (gMG), Pompe disease, Severe combined immunodeficiency disorder (SCID), and Wilson disease. Although Shwachman-Diamond Syndrome was not included in the group of diseases focused on in this study, these results provide evidence to support federal and state policies expanding diagnosis and treatment options for all rare diseases. Importantly, the results from this study were presented on Capitol Hill during the Rare Disease Congressional Caucus Briefing in September. What This Study Found Some key findings from this report include: On average, it takes more than 6 years and nearly 17 doctor visits, hospitalizations, and other health-related trips, to receive a rare disease diagnosis after symptoms begin. The diagnostic odyssey costs individuals and families over $220,000, on average, in avoidable medical bills and lost income — and as high as $517,000 across the 7 diseases studied. There is immense value in timely diagnosis and newborn screening which improve outcomes, both medically and financially. Shortening the diagnostic odyssey saves money for individuals, caregivers, and the healthcare system, while improving health outcomes by providing earlier access to supportive therapies and treatment, delaying or preventing disease complications and physical disabilities, and reducing or eliminating costly and unnecessary services or procedures. Image credit: The Cost of Delayed Diagnosis in Rare Disease: A Health Economic Study Infographic What Can You Do? Make your voice heard: Engage, share your story, and get involved in advocacy. These findings demand attention from researchers, policy makers, healthcare providers, and employers. There is an urgent need to fund research, enhance awareness, and improve access to diagnosis, care, and treatment of rare disease. Contact your elected representatives, share the study findings, and urge Congress and state governments to enhance newborn screening and other policies that facilitate patient access to diagnosis and treatment. __________________________________________________________________________________ The Science Snapshot this week contains content modified from materials distributed by The EveryLife Foundation for Rare Diseases. The Cost of Delayed Diagnosis in Rare Disease: A Health Economic Study EveryLife Foundation for Rare Diseases In Partnership With: The Lewin Group, part of Optum Serve Expert Stakeholders The Rare Disease Community September 14, 2023 Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In this issue: Two new publications by Dr. Seth Corey's group. One comparing genes associated with SDS-like syndrome, and the other on their recent work on zebrafish. Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email connect@SDSAlliance.org or message us on Facebook! This is all for you! New review article by Dr. Corey: Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants The gene that causes SDS in over 90 of patients is the SBDS gene, but other genes have been associated with SDS or SDS-like syndromes as well. The experts have not yet agreed on whether these genes should be considered SDS causing, or rather causing similar but distinct SDS-like syndromes. Dr. Corey's review article is highlighting commonalities on the genes EFL1, DNAJC21, and SRP54 when it comes to symptoms and where they fit into the overall pathways of ribosome and protein maturation. BDS, EFL1, DNAJC21, and SRP54 encode proteins involved in ribosome assembly and nascent polypeptide synthesis. SDS has been viewed as a ribosomopathy. This term has been applied to diverse diseases with germline or somatic mutations, such as Treacher Collins syndrome, DiamondBlackfan anemia, cartilage hair hypoplasia, and del(5q) MDS. The authors "suggest using the term Shwachman-Diamond syndromes or Shwachman-Diamond-like syndrome to denote disorders that may involve blood and/or pancreatic abnormalities, and which result from germline variants that encode proteins affecting ribosome biogenesis and early protein synthesis. The term Diamond-Blackfan anemia should be reserved for those with congenital hypoplastic anemia." The full article is available free (open access): Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants. Kawashima N, Oyarbide U, Cipolli M, Bezzerri V, Corey SJ. Haematologica. 2023 Oct 1;108(10):2594-2605. doi: 10.3324/haematol.2023.282949. PMID: 37226705 New publication by Dr. Corey's group: SBDSR126T rescues survival of sbds−/− zebrafish in a dose-dependent manner independently of Tp53 In this new article, the research team is using their zebrafish model in which the SBDS gene has been deleted. They re-introduce various amounts of functional SBDS protein using genetic tools. The results show that the more functional SBDS protein there is, the better the fish model develops and survives; and that this phenomenon is independent of Tp53. This figure shows a summary of the work. The bottom row are zebrafish embryos that don't have any or enough functional SBDS protein, and therefore cannot develop beyond the early embryo stage. The top row depicts zebrafish that has the normal amount of SBDS protein and therefore develops normally. The rows in the model summarize what happens when there is less than normal amount of SBDS protein or if p53 signaling is disrupted. The full article is available for free (open access). SBDSR126T rescues survival of sbds -/- zebrafish in a dose-dependent manner independently of Tp53. Oyarbide U, Shah AN, Staton M, Snyderman M, Sapra A, Calo E, Corey SJ. Life Sci Alliance. 2023 Oct 10;6(12):e202201856. doi: 10.26508/lsa.202201856. Print 2023 Dec. PMID: 37816584 Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

This September, we took to opportunity to introduce the Shwachman-Diamond Syndrome community at the Chan Zuckerberg Initiative (CZI) Science and Society Meeting in California with a poster presentation focused on the resources and opportunities the SDS community has to offer. We earned a spot at this invitation-only meeting by being an awardee of the CZI Rare-as-One program. The meeting featured incredible success stories of patient advocacy organization in pushing for cures and groundbreaking collaboration opportunities. We are incredibly grateful for being part of this community and the transformative resources the program has bestowed on the SDS community. This poster was created as part of the Scientific Community Engagement Fundamentals course by the Center for Scientific Collaboration and Community Engagement, which Dr. Eszter Hars had the great pleasure to participate in last summer. The poster highlights a variety of aspects of the community, such as Community Overview to describe the community and how the different stakeholder groups and categories interact with each other Community Management to describe how the current de facto community manager is fostering the community and making visible the skills that are at play Community Membership to describe various personas in the community, highlighting what needs we may want to serve Community Value generated through collaboration and why we are investing resources to do this work Community Participation to describe the type of interactions that are involved in various programming and activities, exploring further how a Community Champions program fits in, and highlights Community Programming and future opportunities. Would you like to learn more about this work? Let us know! We can schedule a community presentation and share more individually. About the CZI Science in Society 2023 Annual Meeting: We full-heartedly echo the sentiments shared by CZI: We’re leaving our annual Science in Society Meeting invigorated by the power of partnership and the pivotal role of patients driving scientific progress in rare disease. This meeting was an opportunity for researchers, patients and stakeholders to pool knowledge, forge collaborations and address challenges and opportunities in diagnosis, equity, and the development of treatments and cures. The expanding community dedicated to advancing our understanding of rare diseases is genuinely remarkable!

In this issue: What is Ataluren and what does recent research show about its potential use in treating individuals with SDS in the future? Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! An update on the development of Ataluren, a therapeutic approach targeting the c.183_184TA>CT mutation in the SBDS gene Over the past few years, important research has been ongoing in Dr. Valentino Bezzerri and Dr. Marco Cipolli’s laboratory in Italy to investigate the use of Ataluren to treat individuals with SDS. We previously wrote about this work, including a detailed summary by Dr. Bezzerri in a SDS & Science Snapshot edition from May 2022. Dr. Bezzerri also shared his work at the 2023 SDS POPS summit in May and his presentation is available on the meeting platform (message us if you would like access). And now, we are here to provide you with some updates! This week, the group in Italy published new results of their work. They tested the effect of Ataluren in the laboratory on cells of individuals with SDS who harbor the c.183_184TA>CT mutation in their SBDS gene. These preclinical studies showed: Improved SBDS protein levels and improved ribosome assembly and total protein synthesis; Reduced the elevated levels of p53 protein, which is found in excess in SDS tissues; and Improved migration of neutrophils, important cells in the immune system frequently reduced in individuals with SDS. These results are promising for Ataluren and its use as a "personalized medicine" approach for treating SDS patients carrying nonsense variants, such as c.183_184TA>CT. These preclinical results support the idea of developing of a Phase I/II clinical trial in the future for Ataluren in SDS patients who have a nonsense mutation. The SDS Alliance team will remain in communication with the SDS community about these trials when/if they become available. Be sure to sign up for updates! The figure below summarizes the findings published in the current article. The top of the figure shows what normally happens in SDS cells that harbor a nonsense variant. The bottom panel shows the mechanism of Ataluren and the improvements it makes on the cellular environment. What is the significance of the c.183_184TA>CT mutation in SBDS gene? A large percentage of SDS patients carry the variant (i.e., mutation), c.183_184TA>CT, in addition to the most common “splice site” variant. For instance, the c.183_184TA>CT variant is present in more than half of SDS patients. This genetic change leads to the generation of a premature stop in building the SBDS protein, similar to inserting a period in the middle of a sentence. These types of variants, known as nonsense variants, generally result in unstable protein intermediates and are rapidly degraded in the cell or produce a protein that has lost its function. What is Ataluren? Ataluren (PTC124) was launched in 2007 by PTC Therapeutics (NJ, USA), which promotes careful attention to “incorrect punctuation” in cells (e.g., an extra period in the middle of a sentence). This attention allows for more selective synthesis of proteins with normal structure (i.e., proteins without the extra period in the middle of the sentence). Furthermore, Ataluren has shown less toxicity and better safety than other drugs used for similar purposes. The use of Ataluren as a potential therapeutic agent for genetic disorders has been proposed for the treatment of Duchenne Muscular Dystrophy (DMD) and Cystic Fibrosis (CF). Most importantly, Ataluren has been approved for the treatment of DMD in Europe (but not in the US). Data from clinical trials showed that chronic Ataluren treatment is beneficial to DMD patients undergoing standard care, because it delays the progression of ambulation impairment and the worsening of pulmonary and cardiac functions. Interestingly, clinical studies revealed that the best results are observed in younger individuals, suggesting major benefits of early ataluren administration. Why is Ataluren not widely used? Despite promising pre-clinical results, Ataluren unfortunately failed in clinical studies for CF and was therefore discontinued. This early work suggested there may be highly variable clinical benefits in using Ataluren to treat individuals with CF. Because of such variable levels of effectiveness of Ataluren, it is important to perform extensive preclinical testing using cells in the laboratory, such as the recent work published by Cipolli et al., before trying Ataluren in people with SDS in clinical trials. Find additional information about Ataluren and its treatment of individuals with DMD by watching this YouTube video. __________________________________________________________________________________ Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman-Diamond syndrome cells. Cipolli M, Boni C, Penzo M, Villa I, Bolamperti S, Baldisseri E, Frattini A, Porta G, Api M, Selicato N, Roccia P, Pollutri D, Marinelli Busilacchi E, Poloni A, Caporelli N, D'Amico G, Pegoraro A, Cesaro S, Oyarbide U, Vella A, Lippi G, Corey SJ, Valli R, Polini A, Bezzerri V. Br J Haematol. 2023 Oct 24. doi: 10.1111/bjh.19134. PMID: 37876306. Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

This October, we conducted the 4th annual global virtual fundraiser to support SDS research. The theme this year was 4 MILLION STEPS CLOSER TO #CURESDS. When? October 1-7th, 2023 Where? Virtual! Run/Walk/Roll wherever you like! Plus local events hosted by community members. What? Fun!!! Fundraise and Run/Walk/Roll in your community! Why? To build community and raise funds for SDS research! How? Register here - now closed. See you next year. Event T-shirts were available in our Bonfire store, here! And we created CUSTOM TEAM T-SHIRTS by request. Drumroll, please! Congratulations to John, Jaclyn, Team Nora & Kayla, and Team Declan! You each won in a category of the annual fundraiser for research - 4 million steps closer to #CureSDS. Your prizes will be in the mail, soon. Together, we took over 3 million steps and raised over $7,000! We had 10 fundraising teams, over 100 donors, and 50 people taking the steps challenge. Thank you to all who participated! You all stepped up to the plate to make SDS patients' future brighter. Can't wait for next fall to continue the tradition. Winning team for the most fund raised Winning Team for the steps count challenge Winner of the individual steps count challenge (men) Winner of the individual steps count challenge (women) ​Now in its fourth year, this is the only global, annual fundraising event, dedicated to SDS research. In line with our mission to #CureSDS through our strategy & roadmap, we are raising funds to accelerate therapy and cure development for Shwachman-Diamond Syndrome, a rare genetic cancer predisposition disorder that affects hundreds to thousands of children and adults worldwide. ​ Four million steps are too much for any single person. But together, the steps add up. Together, we can get there! Favorite memories ​ Curious about how we did last year? Check out the 2022 recap, here. The logistics Join the SDS Alliance's 4th annual fun run challenge fundraiser! This is a virtual event and will take place October 1-7, 2023. Everyone is invited to turn hope into action and take steps to #CureSDS - you can walk, run, crawl, roll, swim, or lean back and support those who do by making a donation. The steps and run challenges - step counting, miles, and more - will be managed on the count.it app. We are currently evaluating whether to use their new or classic app, and will make it available mid September. Registered participants will receive detailed instructions on how to join and/or create teams via email prior to 10/1/2023. The main challenge will be step-counting during the week (October 1-7). Let us know if you would like to see additional types of fitness challenges! Invite your family, friends, and neighbors to participate! Registration is free! See the instructions below to learn how you can set up a fundraising page for your child, yourself, or a loved one, and easily invite others to join in your fundraising efforts! As always, 100% of funds raised from the community go to SDS research accelerating therapies, with no overhead! This year, we continue expanding the toolbox for SDS research and start to seed fund drug screens and development as part of our roadmap. Through fundraising and donations, you will play an integral part in driving progress! ​ How to participate: Step 1. Register Register for the 4 Million Steps Closer to #CureSDS fun run by a) setting up a personal fundraising page (team), or b) supporting the fundraiser of your loved one! To set up a personal fundraising page (also known as a team), simply click "I Want To Fundraise For This" on this page, follow the instructions, and customize it with your own content! Everyone loves to see photos of your SDS hero! Pro tip: Add a link to your custom T-shirt campaign from step 2! ​ To register by supporting the fundraiser of your loved one, simply make a donation in any amount to their team/fundraising page! You may have already received the direct link to their page from them. If not, you can find the teams on the main fundraising page. Step 2. T-shirts (optional) Order the event T-shirt to get into the team spirit. We have general event T-shirts, AND we can create custom T-shirts customized with your team name. If you are a team captain, contact us to get your custom T-shirts up and running. Order by 9/14 to receive them in time for the event, and allow extra time for shipping outside the USA. Step 3. Spread the word Share your fundraising page via social media and email and start raising funds for SDS research! Expand your reach by asking family and friends to set up their own fundraisers or promote yours! Increase Awareness! Post photos with your family/friends during the event and let us know who you are running for! Use hashtag #StepsToCureSDS on all social media platforms! Step 4. Walk/run/roll... During the week of October 1-7, hook up your favorite tracker to the count.it app (instructions will be emailed to you) and start taking steps (walk, jog, roll, dance,...) to #CureSDS. Most importantly, have fun! ​ Step 5. Get Rewards ​ Your fundraising efforts are so important and impactful toward accelerating research for therapies and cures, we want to thank you and reward you for your efforts. Raise funds on your personal fundraising page and will send you the following*: ​ Raise $40: Get a canvas tote bag* Raise $400: Get a tote bag, plus an event mug with a delectable chocolate bomb* ​ Challenge winners in each category will get bragging rights and both gifts* above! ​ *Items are subject to change, and we will reach out to you first to confirm your shipping address, preferences, and size. ~~~~~~~~~ Questions? Email us at connect@SDSAlliance.org

In this issue: New research contributes to knowledge on how we can improve bone marrow failure surveillance in SDS Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! Framework for Risk-Stratification of Bone Marrow Failure Surveillance in SDS At the end of the summer, Dr. Warren and colleagues in the United Kingdom published results from an important study of theirs which helps explain why individuals with SDS are at such high-risk for developing bone marrow failure and leukemia and how we can improve bone marrow surveillance. Dr. Warren's work helps build upon research previously published by Drs. Shimamura and Reilly regarding bone marrow failure surveillance in inherited bone marrow failure syndromes (featured in our SDS & Science Snapshot Series earlier this year!). We reached out to Dr. Warren to bring you an exclusive summary of their work. Here is what they shared: This study examined the DNA of blood cells from 10 people with Shwachman-Diamond syndrome (SDS) to see how their blood cells change over time. The work shows that many blood cells in SDS acquire mutations that converge on the genes involved in making ribosomes (the machines that make proteins in the cell) or are components of the machinery that senses the integrity of the ribosome assembly process. The acquired mutations were recurrent, mutually exclusive between different colonies and arise early in life, even in utero and may then persist for decades. Only a limited set of blood stem cells are producing about half the total number of blood cell colonies by young adulthood. These findings explain why the blood system in SDS is particularly vulnerable to cancer due to loss of function mutations in a gene called TP53, the so called “guardian of the genome” that normally protects against cancer. The study also noted that blood cancer cells in SDS have an increased overall number of mutations, likely reflecting the capacity of these cells to grow rapidly. This study forms a framework for better risk-stratification in SDS, where patients merit close monitoring of emergent clones. Given the large number of single-hit TP53 clonal expansions that many SDS individuals have, each potentially serving as a substrate for evolution to blood cancer and the very rapid outgrowth and genomic evolution observed following the acquisition of TP53 mutations, consideration for early therapeutic intervention, such as bone marrow transplantation, may be warranted. a Defective germline ribosome assembly in SDS causes cellular stress, resulting in accumulation of TP53 clones and increased cell death. b Adaptive somatic mutations can help restore ribosome homoeostasis and decrease accumulation of pathogenic TP53 mutations that would result in clonal evolution. For more information regarding clones and clonal hematopoiesis, please refer to our video (2021), SDS Science SPOTLIGHT Series: Clones - The Good, the Bad, and the Ugly. Convergent somatic evolution commences in utero in a germline ribosomopathy. Machado HE, Øbro NF, Williams N, Tan S, Boukerrou AZ, Davies M, Belmonte M, Mitchell E, Baxter EJ, Mende N, Clay A, Ancliff P, Köglmeier J, Killick SB, Kulasekararaj A, Meyer S, Laurenti E, Campbell PJ, Kent DG, Nangalia J, Warren AJ. Nat Commun. 2023 Aug 22;14(1):5092. doi: 10.1038/s41467-023-40896-5. PMID: 37608017 Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In this issue: What are germline genetic variants and how are these different from somatic variants? Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you! Understanding the Role of Genes: Somatic and Germline Variants Our bodies are composed of trillions of cells that have many different roles – to help us grow, digest food, protect us against infections, and more. These different tasks are controlled by a set of instructions known as genes. (We even have genes whose purpose is to protect us against cancer!) Genes are made up of DNA, which you inherit from your parents, and they determine things like your eye color, height, and even your risk for certain health conditions. Germline variants (i.e., mutations) are genetic changes that are present in the reproductive cells (egg and sperm) and can be passed on to the next generation. Shwachman-Diamond Syndrome is caused by germline variants in specific genes, most commonly the SBDS gene. These germline variants are inherited from one or both parents and are responsible for the development of SDS in affected individuals. This is in contrast to somatic variants, which are changes in the DNA that happen in the cells of the body during a person's lifetime. These variants are like “typos” that can occur as your cells divide or can occur as a result of harmful exposures such as smoking, alcohol consumption, aging, radiation, or other environmental factors. Somatic variants can lead to various health issues or diseases, such as cancer, but they are not inherited from one's parents and do not affect future generations. Identifying potential somatic variants driving cancer growth and development could have implications for potential treatment options and estimating recurrence risk and prognosis. We have recently created an educational video on the genetics of SDS. We cover the concept of germline versus somatic variants (around minute 5), and how they related to leukemia. The image below compares germline variants (left panel) to the development of somatic variants (right panel). Stay tuned for our Science Snapshot next week to see how this information relates to new research regarding somatic variants in Shwachman-Diamond Syndrome! __________________________________________________________________________________ For more information regarding the difference between somatic and germline variants, you can visit the Cleveland Clinic’s website. The featured image is courtesy of the NHS: Genomics Education Programme. __________________________________________________________________________________ Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post:

In Loving Memory Moe passed away from complications of stem cell transplantation 200 days post transplant, surrounded by his family. He leaves behind his wife, two teenage daughters, his parents and siblings, and countless family and friends. If you would like to support his family, please consider donating to the GoFundMe page the family has set up at the start of his transplant journey: https://gofund.me/7909aa8d Here is what the family shared: July 23, 2022 "We are starting a Go Fund Me with the recommendation of his Team. It was recommended because this procedure is going to be financially difficult for Moe and Lauren. As a family we prepared by allocating and coordinating food shopping, electric bills, heating bills, future bills, etc. but not prepared for the astronomical costs involved for his month long chemo stay, the 35 daily oral medicines, co-pays and daily organ protection injections. The cost is projected to be well over $100K. Moe is currently at Dana-Farber and in the process of a bone marrow transfer due to the development of Myelodysplastic Syndrome, which can develop into acute myeloid leukemia. Moe has been with Dana-Farber for well over 5 years and been anxiously waiting for this day to come. The Post-Office will provide him with 6-weeks of salary but after that will be down to Lauren’s teacher salary and Moe's social security. Moe’s recovery will continue on for a year at minimum which means he can’t work for well over a year and until he can get his second round of childhood vaccinations. In fact, he can not eat anything other than frozen food and food prepped by Lauren. History of our Moe: Moe was born with Shwachman-Diamond Syndrome named by two doctors Diamond and Shwachman. For the first year of his life he lived in the hospital malnourished not being able to digest fats from foods and neutropenic (low blood cells). It was literally the grace of God that my parents crossed paths with a very special doctor at Children’s Hospital in 1982, Dr. Diamond. At an early age, he was given a very short life expectancy. With the strength and doctor-like qualities our parents provided him, he made it through each and every single night sick and deathly and lived a fairly “normal” childhood. There is just so much leading up to this moment and I could go on and on with past health trauma and the struggle of living with a disease such. Please know that as family we all had the understanding and knew that this was going to be the outcome should he live past the expectation of this disease. Although frightening and all other imaginable emotions involved, we are just so excited that when the bone marrow begins to build and new cells develop that he will NEVER have to worry about this form of bone marrow failure again. One other important piece to this journey is that Moe has been blessed with two donors and they are 10/10 matches, his sister Tiffany and brother Joey. They have both stepped up and said YES without hesitation. Tiffany was chosen and is already prepped and ready for intake. Her 3-hour procedure of removing healthy cells from her body and giving them to Moe will happen on July 27th. We thank you all so much and just so blessed to have such amazing friends and family supporting Moe. From the bottoms of our heart and bone marrows, we thank you ❤️" February 4, 2023 "Day +192: A lot has happened since our last update. Moe’s transplant was going well; attending weekly, then monthly doctors appointments. Experienced minor GVHD of gut, but overall was going smoothly. About 3 weeks ago, just shy of 6 months post transplant, Moe started having some trouble breathing. Just assumed it was some congestion/ cold, but no fever. After a couple days, we went to the ER because it wasn’t getting any better. They diagnosed him with organized pneumonia; unsure what caused it though. After 3 days, he was moved to the ICU because he needed more supportive oxygen. He started getting better after a week, however, they think he may have then aspirated into his lungs, making it worst. On January 23, they decided to intubate him and put him on a ventilator. He was not making much progress, however, was stable. Yesterday, after being on the ventilator for almost two weeks, they decided he needed a tracheostomy. Although slow, he has made slight progress this week. The doctor said it’s going to be a long difficult road, and will probably get worse before it gets better, but they are hopeful that he will make a recovery. We cannot thank everyone enough for your thoughts, prayers, and support. We are so fortunate to have such a strong community behind us. #MoeStrong #TeamMoe" Moe passed away surrounded by his family on February 12, 2023. He was 41 years old. Obituary Maurice “Moe” Giordano III – Age 41, beloved husband of Lauren M. (Edie) Giordano died peacefully Sunday at the Brigham and Woman’s Hospital in Boston with his family at his side. He was born in Lowell, April 14, 1981, a son of Michelle Granfield of Billerica and Maurice Giordano Jr. and Laura Giordano also of Billerica. He attended Billerica Schools and graduated from Billerica Memorial High School in 2000. Moe was blessed with a large and loving family and spent a lot of time together. He married his high school sweetheart and have been together the last 24 years. He was a wonderful dad to his two cherished daughters; always attending their activities, father-daughter dances, and making them feel special. Moe was employed as a Mail Carrier for the U.S. Postal Service in Billerica for the past 22 years. He was so proud of working there and enjoyed seeing his post office friends and customers each day. Moe loved following sports, including the Patriots and Red Sox, collecting sport cards with his nephews, coin collecting with his brother, golfing with his friends, vacationing with his family, driving his Mustang Convertible, working in his yard, going to arcades & candy stores, watching movies, listening to country music, and playing with his dogs. He was always there whenever anyone needed a helping hand Besides his wife and parents, Moe is survived by his daughters, Madison and Alexis Giordano of Billerica; his sisters, Melissa and her husband James Gaffney of Bedford, NH and Tiffany and her husband Michael Ostrander of Merrimack, NH; his brother, Joseph Giordano and fiancé Kerrianne Larson of Billerica; his maternal grandmother, Ruth O’Toole of Billerica, his mother and father-in-law Bob and Lorna Edie of Billerica, Brother and sister-in-law Shane and Tara Edie of Lunenburg, nieces and nephews James “JJ” and Stephen Gaffney, Joseph Giordano, Scarlette and Dominic Edie, and Andrew and Addison Ferola, and his fur babies Fenway, Jillette and Tuxy. He also leaves behind many aunts, uncles, cousins, and friends. He is predeceased by his maternal grandfathers Stephen O’Toole and Joseph Granfield, paternal grandparents Maurice Sr. and Cecile Giordano, and brother-in-law Robert Edie Jr.

Shwachman-Diamond Syndrome receives new ICD-10 Diagnostic Code, Paving the Way For Improved Patient Care and New Treatment Options. Code D61.02 goes into effect October 2023. Woburn, MA (August 8th, 2023) — In a monumental leap forward for Shwachman-Diamond Syndrome research, treatment, and patient care, the Shwachman-Diamond Syndrome Alliance is thrilled to announce that the US version of the authoritative international diagnostic manual will soon include a unique diagnostic code for Shwachman-Diamond Syndrome — a rare genetic disorder with often devastating outcomes for patients, first described in 1964. In its latest revision, the International Classification of Diseases, Clinical Modification (or ICD-10-CM) officially recognizes Shwachman-Diamond Syndrome as a distinct disease, with code D61.02 going live October 2023. This change could pave the way for improved treatments, novel therapies, and someday a cure. Dr. Eszter Hars, Ph.D, President and CEO of SDS Alliance, elaborates: “This represents a major milestone for the SDS community; one that will be instrumental in future progress for better understanding and better treatments for SDS patients worldwide. By assigning this ICD-10-CM code, the CDC is formally recognizing SDS as a discrete and important disease worthy of tracking and coding in the ICD system, and that will make a life-altering difference for people affected by the condition.” Previously, SDS was not coded as such in medical records. Instead, healthcare professionals resorted to using general ICD-10 codes, which encompass multiple conditions or individual symptoms but aren't custom tailored for SDS. While such codes may have sufficed for insurance purposes, they fell short when it came to tracking or understanding the journey of SDS patients within healthcare systems. SDS was essentially invisible. Dr. Hars explains further, “This specific and unique code for SDS will help provide invaluable insights and data into the number of patients, the range and severity of symptoms, as well as the types and timing of treatments, testing, and services they receive, and the outcomes of those interventions. It will also help simplify and streamline the insurance reimbursement process for patients and make it easier to receive the most appropriate and beneficial medical care, tests, treatments, therapies, and services.” Most importantly, Dr. Hars stresses, the change will help accelerate therapy development by capturing new data that is crucial for driving further investments in research. “The newly approved ICD-10 code for Shwachman-Diamond Syndrome will improve patient care for individuals with SDS,” said Dr. Lisa McReynolds, of the National Cancer Institute, part of the National Institutes of Health. “Insurance approvals will be easier to process, and medical records will be standardized, facilitating research on this rare syndrome. This is a milestone achievement for the SDS Alliance that will benefit all SDS patients, including those enrolled in the NCI Inherited Bone Marrow Failure Syndrome study (NCT00027274).” Shwachman-Diamond Syndrome: A Brief Overview Shwachman-Diamond Syndrome is a distinct genetic condition characterized by the body's inability to produce adequate amounts of protein, which plays a pivotal role in every cellular and organ function and is fundamental to life. Consequently, many of the body's systems are adversely impacted in SDS patients. To create new proteins, the body relies on sub-cellular structures called ribosomes to perform the complex assembly. Ribosomes work much like hands assembling LEGO towers, but instead of plastic blocks, they stack amino acids in specific patterns to build a variety of proteins. The specific sequence of amino acids, as determined by the genetic code found in DNA, is what dictates the proteins’ three-dimensional shape and, ultimately, their function. A genetic anomaly found in SDS patients results in their cells being unable to form enough functional ribosomes, leading to an overall decline in protein synthesis. This deficiency manifests differently across patients and their respective organs, resulting in a range of symptoms. Many individuals with SDS encounter digestive issues and pancreatic challenges that can lead to malnutrition, pain, and failure to thrive. Others face complications with their immune system, making them prone to frequent or severe infections and hospitalization. Additionally, some patients grapple with cognitive issues, which can cause learning and behavioral challenges. Notably, by the age of 30, approximately one-third of those with SDS will confront grave complications related to their bone marrow, such as aplastic anemia and leukemia — the latter being particularly alarming due to its dire prognosis. Diagnostic challenges can further complicate matters. A significant number of SDS patients face misdiagnoses or endure prolonged waiting periods before receiving an accurate diagnosis. Such delays can result in undue distress, unnecessary invasive procedures, ineffective treatments, and in grave cases, even death from leukemia and other associated complications. The most reliable method for diagnosing SDS is genetic testing; specifically, identifying the presence of mutations in the SBDS or other genes responsible for the disorder. For the well-being and longevity of SDS patients, it's imperative that diagnosis is both swift and precise. The Long, Arduous Path to ICD-10-CM Classification The path to obtaining a new code for a previously unclassified disorder involves a long and challenging process. In the US, the CDC’s ICD-10 Coordination and Maintenance Committee selects proposals for live presentations either at its headquarters in Baltimore or virtually twice a year. In December 2021, the SDS Alliance, aided by Medical Advisory Board member and NICER consortium director Dr. Kelly Jo Walkovich, University of Michigan, C.S. Mott Children's Hospital, along with collaborator Dr. Alison A. Bertuch, Texas Children's Hospital and Baylor College of Medicine, submitted a proposal for a new code. Their proposal was then selected for presentation at the March 2022 meeting. During the public comment period that followed, major organizations such as the NIH IBMF study, the American Society of Hematology, the Leukemia and Lymphoma Society, the Aplastic Anemia & MDS International Foundation, and The American Society of Pediatric Hematology/Oncology, submitted letters of support. The new code was officially accepted in July 2023 and will be active starting October 1st, 2023. The SDS Alliance credits Dr. Terry Jo Bichell from COMBINEDBrain for her guidance and support throughout the effort. Dr. Bichell explains, “Because rare genetic disorders like SDS will likely be treated based on their underlying genetics and molecular mechanism, unique ICD-10 codes for each genetic disorder are crucial to identify, track and treat patients. This new code will help patients with SDS get the medical care they need. We at COMBINEDBrain are proud of the SDS Alliance for their work on this, and we are grateful to the CDC committee for recognizing the necessity of a code for Shwachman-Diamond Syndrome.” The International Classification of Disease The ICD is a collaborative effort by the World Health Organization, the Centers for Medicare and Medicaid Services, and the Centers for Disease Control and Prevention. It is a global tool that allows medical professionals, insurers, and public health experts to categorize and code healthcare-related encounters. Launched by WHO in 1948, the ICD has seen multiple revisions. The 10th version was ratified in 1994, with US adoption following later. While the WHO approved the updated ICD-11 for introduction in 2022, US adoption will likewise lag by a few years. In the meantime, the US continues with ICD-10, ensuring the newly added SDS code remains active. The Shwachman-Diamond Syndrome Alliance The SDS Alliance is a 501(c)(3) nonprofit organization dedicated to building a world where all patients affected by Shwachman-Diamond Syndrome can live full lives. The SDS Alliance focuses on driving research and paving the path toward therapies and cures by funding and coordinating research, building research tools and infrastructure, and fostering advocacy, collaboration, and knowledge sharing. The SDS Alliance brings together patients, caregivers, researchers, clinicians, and other diverse stakeholders to better understand, diagnose, and treat this devastating genetic cancer predisposition disorder. The SDS Alliance was launched in 2020 by the parents of a child with SDS, both of whom are biomedical researchers and entrepreneurs. Learn more at www.SDSAlliance.org North American Immuno-Hematology Clinical Education & Research Consortium (NICER) The mission of the NICER consortium is to provide a collaborative multidisciplinary environment to advance the education, clinical care, and research involving pediatric and adult patients with immuno-hematologic disorders. The target patient population encompasses all disorders within immuno-hematology including those with complex immune cytopenias, bone marrow failure, lymphoproliferative and histiocytic disorders, immune deficiencies, autoinflammatory disorders and immune dysregulatory syndromes along with emerging phenotypes of a similar nature. Given that institutional referral patterns and expertise vary, NICER is committed to being purposefully inclusive of pediatric and adult providers from multiple disciplines including, allergy/immunology, genetics, hematology/oncology, hematopoietic stem cell transplant, rheumatology, infectious disease, gastroenterology, endocrinology, etc. to enrich the educational environment and research goals of the consortium. Learn more at www.nicerconsortium.org/ NCI Inherited Bone Marrow Failure Syndrome Study (NCT00027274) Inherited bone marrow failure syndromes are a group of rare disorders of the bone marrow that can result in a number of medical conditions, including a high risk of cancer. Over the past several decades, researchers and clinicians at the National Cancer Institute have studied individuals with these syndromes in order to better understand their genetic causes and medical complications. Their overall goal is to improve the health care for persons with these disorders. The NCI IBMFS Cohort Study enrolls families that have at least one member with an IBMFS, such as Shwachman-Diamond Syndrome. There have been many medical advances as a result of the study, including the identification of several new genetic causes of IBMFS. Learn more at www.marrowfailure.cancer.gov/ibmfs COMBINEDBrain The Consortium for Outcome Measures and Biomarkers for Neurodevelopmental Disorders is a non-profit organization devoted to speeding the path to clinical treatments for people with rare genetic neurodevelopmental disorders by pooling efforts, studies and data. More Information Visit the ICD resource page of the SDS Alliance at www.sdsalliance.org/icd Media Contact Eszter Hars, Ph.D. President and CEO, Shwachman-Diamond Syndrome Alliance connect@SDSAlliance.org

In Loving Memory Rycroft passed away last month at the age of 16 months following a bone marrow transplant, which was needed due to Shwachman-Diamond Syndrome (SDS). His parents are sharing his story to raise funds for the hospitals that provided outstanding care for Rycroft and their local SDS organization (SDS UK) which provided support during Rycroft's challenging SDS journey. Rycroft's parents Andrew and Catherine shared the heartbreaking news on Twitter: Rycroft was a happy, shouty, beautiful little boy and it seemed like everyone that met him fell in love with him. He loved to crawl, even though his condition made it hard for him to lift his head. So he crawled backwards and upside down. He was surprisingly speedy. Rycroft was a world champion sleeper. With no soothing or assistance of any kind from us, he could be sparko in seconds. He would wrap his favourite toy, BunBun, around his head and that was the sign he was off to . BunBun is still with him now, friends to the end. Rycroft seemed to like Status Quo and other DadRock. He'd certainly bash his toys along to the music. If that was actually a sign you wanted it turned off, then sorry Rycroft. People with SDS are much more likely to need bone marrow transplants than the general population. We think Rycroft may have been the youngest SDS patient in the UK ever to receive one, and perhaps the third youngest worldwide. The transplant went well, but he later developed an infection in his lungs, and was transferred to ICU. He had to be sedated and put onto a ventilator. I found it difficult to be with him, him virtually motionless, me feeling like a spare part during my son's toughest hours. What I found really helped was reading to him. I read him all of William the Conqueror by Richmal Crompton. Like William, Rycroft was a little boy with a dog called Jumble. And as @monstroso says in his introduction, William is what every boy wants to be, a hero. As was Rycroft. There came a point where we realised that Rycroft was not going to recover. @GreatOrmondSt were amazing at taking us through that realisation. When Rycroft died, it was peacefully in our arms. We got the chance to tell him how much we loved him and how much he means to us. It's hard to believe that we will never see him again. But in sixteen months, he gave us a lifetime's worth of happiness. Right now, we really want to do what we can to support other families like ours, other children like Rycroft, through [three charities we chose]. Whatever you can give, whatever you can do to share, spread the word - thank you. Andrew and Catherine set up a JustGiving fundraising page in memory of Rycroft: Our beautiful baby boy Rycroft passed away aged just 16 months. He was a smiley, sociable and inspirational little boy who charmed everyone who met him. Rycroft suffered from Shwachman Diamond Syndrome (SDS), a rare genetic condition that affects multiple systems within the body and, in a quarter of cases, results in bone marrow failure. For a huge proportion of his short life he was cared for by the wonderful team on the children’s ward at Colchester General Hospital. In March 2023 he was admitted to Great Ormond Street Hospital for a bone marrow transplant – and although the transplant was initially successful, he passed away a few months later after contracting a subsequent infection. We are devastated by his loss and want to raise funds to help other families who may go through what we have been through, and to raise awareness of the incredible work of the medical professionals who cared for him. We have chosen three charities that do amazing work to help children like Rycroft survive and thrive. Great Ormond Street Hospital, Fox Ward Colchester Hospital, Children's Ward SDS UK All funds donated will be split evenly and will go to support these charities, who played such a huge role in giving Rycroft and us 16 wonderful months together, and give us hope that other families in a similar position will see their children grow up to live full and happy lives. Thank you, Andrew and Catherine

In this issue: Comprehensive review article on bone marrow surveillance of SDS patients by Drs. Shimamura and Reilly; and a recap of ASH 2022, the biggest annual professional conference on hematology in the world. Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email connect@SDSAlliance.org or message us on Facebook! This is all for you! New comprehensive review article on the benefits and need for bone marrow surveillance in SDS patients Fresh off the press, a new review article by Dr. Shimamura and Dr. Reilly was published on December 21, 2022, titled Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances. This is a detailed review article that summarizes many of the key features and challenges in SDS, in particular the leukemia risk, bone marrow biopsies for monitoring, and transplant considerations. As we all know, Shwachman-Diamond syndrome (SDS) is an inherited multisystem ribosomopathy characterized by exocrine pancreatic deficiency, bone marrow failure, and predisposition to myeloid malignancies. The article provides an overview of the pathobiology of SDS, which is a scientific term for the mechanism within the cell that causes the problems in SDS as a result of the mutations underlying SDS. SDS results from impaired ribosome maturation, i.e. the cell is not able to assemble as many ribosomes as it normally needs. We have created a video about this previously. The article highlights that the outcomes for SDS patients who develop myeloid malignancies (i.e. acute myeloid leukemia, AML, a specific type of blood cancer) are still extremely poor. This is because SDS patients are highly sensitive to chemotherapy and also because this type of leukemia is a very hard to treat in general and often comes back even after a successful hematopoietic stem cell transplant (HSCT). Data from the North American SDS Registry indicate that outcomes are improved for SDS patients who undergo routine bone marrow surveillance - i.e. bone marrow biopsy and aspiration and then examining the samples with several kinds of tests - and receive a HSCT prior to developing leukemia. This article sets the stage to evaluate what the optimal approach to hematologic surveillance and timing of HSCT for SDS patients may be, what to look for, and what types of testing are recommended. The article also summarizes recent studies regarding the distinct patterns of somatic blood mutations in SDS patients that either alleviate the ribosome defect by somatic rescue (heterozygous EIF6 inactivation) or disrupt cellular checkpoints resulting in increased leukemogenic potential (heterozygous TP53 inactivation). This concept is complex but really important in SDS. If you would like to learn more, check out our video from 2021: Clones in SDS: The good, the bad, and the ugly. The article presents and summarizes evidence supporting hematologic surveillance for SDS patients that incorporates clinical, pathologic, and molecular data to risk-stratify patients and prioritize transplant evaluation for SDS patients with high-risk features. The field of clonal hematopoiesis - especially when it comes to genetic predisposition to malignancy such as SDS - is fairly new. We would like to thank Dr. Shimamura, Dr. Reilly, and Dr. Lindsley, for the groundbreaking work in this area and their efforts to provide these insights and spread awareness to the medical community. Looking into the future, we need the international hematology and SDS community to come together and develop a consensus on how SDS patients should be monitored, what genetic changes should be tested and what they mean, so that all patients - regardless of where they are - can be confident that they receive adequate care. We are ready to support the process. Additionally, we are calling on all SDS patients to consider participating in the North American SDS Registry and all other clinical registries in their geographic area to support important work such as this. A list on clinical registries is available on our website, here: https://www.sdsalliance.org/sds-registries The full-text article is currently behind a paywall, but the abstract is publicly available. Please reach out if you need access to the full text. [Update: as of summer 2023, the article is now available open access using the same links posted here] Predisposition to myeloid malignancies in Shwachman-Diamond syndrome: Biological insights and clinical advances. Reilly CR, Shimamura A. Blood. 2022 Dec 21:blood.2022017739. doi: 10.1182/blood.2022017739. Online ahead of print. PMID: 36542827 Recap of ASH 2022 The 64th American Society of Hematology (ASH) Annual Meeting was held last month, from December 10-13 in New Orleans, Louisiana. Dr. Hars, as a representative of the SDS Alliance Non-Profit Patient Advocacy Organization, have been awarded complimentary registration to the 2022 ASH Annual Meeting & Exhibition (a $1,500 value) as an appreciation of our organizations’ continued effort and dedication to the patients and the field of hematology. We would like to thank the organizers of ASH for this opportunity! According to ASH, there are “typically, more than 5,000 scientific abstracts submitted each year, and more than 3,000 abstracts are accepted for oral and poster presentations through an extensive peer review process.” In fact, doing a quick search on the now publicly available abstracts’ page, we found close to 6,500. Importantly, there are several abstracts, posters, and talks about SDS or relevant to it. Here is our brief overview. Related to the review article features above in this week's snapshots article, Ashley Galvin - in collaboration with the North American SDS Registry - presented an oral and poster abstract titled: Outcomes of Hematologic Complications in Shwachman Diamond Syndrome: High Risk Features and Implications for Surveillance "AML carries a poor prognosis for patients with SBDS mutations, so early referral for novel therapies should be considered. Marrow surveillance including morphology, cytogenetics, FISH, and somatic mutation analysis identified patients who developed HRF (High Risk Features). Survival was excellent for patients transplanted for HRF. Although SDS is rare and patient numbers are small, these data show that regular comprehensive marrow surveillance can identify HRF to inform the need for closer monitoring or transplant prior to progression to malignancy." SDS was also covered in an Education Program session titled: What is New in Classical Bone Marrow Failure Syndromes? (focus on management) Inherited bone marrow failure syndromes are a complex set of disorders characterized by single or multilineage cytopenias and elevated risk of hematopoietic and other malignancies. Patients may present with classic phenotypes, such as neutropenia in Shwachman-Diamond Syndrome, but the increased use of germline genetic testing and other diagnostics have led to a growing appreciation of a wide spectrum of IBMFS [inherited bone marrow failure syndromes] clinical phenotypes and ages at onset ranging from children to adults. This educational session explored the clinical manifestations, genetic etiologies, and new avenues for the management of severe congenital neutropenia [including Shwachman-Diamond Syndrome], Fanconi anemia, and telomere biology disorders. Dr. Jean Donadieu (Service d'Hémato-Oncologie Pédiatrique, Hopital Trousseau, Paris, Cedex, France and director of the French congenital neutropenia registry) discussed therapeutic options for severe congenital neutropenias (SCNs) beyond granulocyte colony stimulating factor (GCSF) and hematopoietic cell transplantation, using three different genetic disorders as examples. First, the talk described the rationale for the use of inhibitor of sodium glucose cotransporter (ISGTL2), an anti-diabetic drug, in glycogen-storage disease type-IB and glucose-6-phosphatase catalytic subunit-3 (G6PC3) neutropenias; Second, a potential role of C-X-C chemokine-receptor-4 inhibitors in warts, hypoglobulinemia, infections and myelokathexis (WHIM) syndrome. And third, it discussed the concept of stimulating somatic genetic rescue, a physiological process that might limit the risk of leukemic transformation, like EIF6 inhibitors in Shwachman Diamond Syndrome - an area of focus in several research labs. Dr. Carlo Dufour (G.Gaslini Chidlren's Hospital, Genova, Italy) focused on management of Fanconi Anemia and its clinical complications starting with presenting a case report that outlines the importance of a long-term specific monitoring plan in this setting. The talk will outlined monitoring strategies tailored to timely detect hematological complications in order to perform hematopoietic cell transplantation (HCT) in optimal conditions. The most recently adopted HCT platforms was discussed. This talk also addressed surveillance approaches to identify early cancers, especially epithelial cancers of head and neck and urogenital regions, that currently have no satisfactory treatment. Dr. Sharon Savage (Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD) discussed the numerous genetic discoveries and the advent of clinical telomere length testing that have led to the recognition of a spectrum of telomere biology disorders (TBDs), beyond classic dyskeratosis congenita (DC). While hematopoietic cell transplantation and androgen therapy are effective for bone marrow failure in TBDs, there is a paucity of options for the other manifestations, such as pulmonary fibrosis, liver disease or cancer. This talk highlighted areas in need of additional clinical and basic science research while providing the background for clinical diagnosis and management. Another way to look at SDS is by comparing it to other neutropenias caused by different genetic disorders. Dr. Maksim Klimiankou (Department of Hematology, Oncology, Clinical Immunology, University Hospital Tuebingen, Tuebingen, Germany) presented an oral and poster abstracts on this topic, titled: Accumulation of Specific Somatic Leukemia-Associated Mutations in Congenital Neutropenia Precedes Malignant Transformation – New Preconditions for Treatment Decisions There were several abstracts submitted on model systems, namely three on zebrafish and one on mouse: Dr. Usua Oyarbide (Department of Cancer Biology, Cleveland Clinic, Cleveland, OH) presented an abstract titled: Deletion of eif6 Partially Rescues Survival, but Not Neutropenia, of Zebrafish Model of Shwachman-Diamond Syndrome: The Roles of Sbds and Eif6 in Perturbing Lipid Metabolism "We conclude that the organismal models of sbds or eif6 deletion provide new insights into the pathophysiology of human SDS: 1) SBDS affects lipid metabolism possibly due to an accumulation of EIF6, 2) Loss of eif6 affects development/survival at an earlier stage than loss of sbds, and 3) Loss of either sbds or eif6 markedly upregulates cdkn1a, which is downstream of tp53. Interestingly, Eif6 partially rescues survival of sbds-null organisms, but only in the haploinsufficient state. EIF6 may offer a promising target for a novel therapeutic strategy in SDS." Dr. Nozomu Kawashima (Cleveland Clinic Dept of Cancer Biology, Cleveland) presented an abstract titled Deletion of efl1 in Zebrafish Recapitulates the Spectrum of Shwachman-Diamond Syndrome "Zebrafish lacking efl1 phenocopied some of the molecular and morphologic features of SDS. Additionally, results from efl1-/- zebrafish were consistent with those from sbds-/- zebrafish strains, emphasizing a common molecular pathway induced by the dyad of EIF6 dissociating factors. Ongoing studies, which will be presented, are evaluating skeletal abnormalities and pancreatic atrophy in the efl1-/- zebrafish. Interestingly, sbds-null and efl1-null fish survived longer than eif6-null, suggesting more critical functions of EIF6. Altogether our data and presented elsewhere advance the hypothesis that CDKN1A and EIF6 contribute to the pathophysiology of SDS due to either mutations in SBDS or EFL1." Dr. Sarada Ketharnathan (CHEO Research Institute, Ottawa, ON, Canada) presented an abstract titled: A Zebrafish Model of Dnajc21 Deficiency Identifies Essential Roles in Granulocyte Differentiation and Metabolic Regulation "Our findings suggest that Dnajc21 is required for normal granulocyte differentiation and cell proliferation. We also identified previously unrecognized roles for Dnajc21 in regulating cellular metabolism. We propose that the zebrafish models described here readily serve as in vivo platforms to identify therapeutic compounds that restore normal hematopoiesis and prevent leukemic transformation in SDS." Dr. Michael Peters (Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA) presented an abstract titled Targeting a Putative Intronic Splicing Silencer Salvages Expression from the Recurrent SBDS C.258+2T>C Mutant Allele in Shwachman-Diamond Syndrome Patient Cells and Mouse Model "[..] Disruption of sequences within this putative ISS by Cas12a nuclease-mediated indels result in 1.4 and 2.4 fold increased SBDS/Sbds expression from SDS patient fibroblasts and homozygous MEFs respectively (p<0.05). Together these studies present a novel mouse model for SDS recapitulating the recurrent SS mutation with residual intact splicing and indicate that salvaging residual SBDS expression by modulating aberrant splicing is a promising strategy for SDS therapeutics." We applaud all the researchers from around the world who work on SDS and bring us closer to therapies and cures. A heartfelt THANK YOU on behalf of the SDS Alliance and the patient community! Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on top right of this post: