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In this issue: SDS Alliance highlights the patient voice at the international INNOCHRON meeting in Greece! 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! What is EuNet-INNOCHRON? EuNet-INNOCHRON is an ACTION OF EUROPEAN COOPERATION IN SCIENCE AND TECHNOLOGY, and is an abbreviation for European Network for Innovative Diagnosis and Treatment of Chronic Neutropenias. Chronic neutropenias (CNP) represent a wide spectrum of disorders ranging from mild to life-threatening, acquired or congenital diseases. Shwachman-Diamond Syndrome is part of this category, specifically part of the congenital neutropenia subtype. The pathophysiological mechanisms underlying CNPs are diverse and vary from haemopoietic stem cell and bone marrow microenvironment defects resulting in impaired neutrophil production, to immune disturbances leading to accelerated apoptosis of neutrophil progenitors and/or the circulating mature neutrophils. The prognosis of patients with CNP is related to the underlying pathogenesis, the degree of neutropenia and the propensity for leukaemic transformation. Accurate diagnosis is mandatory for risk stratification and treatment choice. The principal challenge of the Action is to establish a wide network of researchers with special interest in CNPs and facilitate interactions and collaborations among top-level European experts and young investigators from different scientific areas i.e. Clinical and Laboratory Haematology, Immunology, Genetics, Molecular Biology and Regenerative Medicine. The main aims of the Action are: to promote science, training and education on advanced biochemical, immunological, genetic and molecular biology techniques for the accurate diagnosis and treatment of patients with different types of CNP, early recognition of Myelodysplastic Syndromes/Acute Myeloid Lekaemia evolution and appropriate intervention, to link and further expand existing neutropenia networks for a more multidisciplinary approach of CNP that will result in a better characterization of the underlying diseases and development of individualized and precision medicine therapeutic approaches for selected patients, to organize and expand CNP patient Registries and Biobanks using homogenized protocols in line with the ethical standards of the European Legal Framework and the relevant national regulations. How did the SDS Alliance highlight the patient voice? The SDS Alliance was invited to present the patient perspective and our advocacy efforts, and the organizers were very accommodating by providing virtual access to this impactful in-person meeting. Dr. Hars focused her talk on two areas. First, she shared patient stories and the impact SDS has on patients and their families. Second, she highlighted the SDS Alliance's programs to accelerate research toward therapies and cures. These focus areas and their progress are also highlighted on our website on our Strategy & Roadmap page . What was the Final Conference and Working group meeting about? The Final Conference of EuNET-INNOCHRON (European Network for the Innovative Diagnosis and Treatment of Chronic Neutropenias) Research Newtork - a COST Action - focusing on research in the field of chronic neutropenias, took place April 4-6, 2024 at the KAM Center of Mediterranean Architecture in Chania, with limited virtual access to selected speakers. The chair of the COST Action CA18233 EuNet-INNOCHRON, Helen Papadaki, Professor of Hematology School of Medicine, University of Crete and Director of the Hematology Department of the University Hospital of Heraklion UHH (PAGNI), organized the conference, with the participation of researchers from 32 countries as well as the European Hematology Association (EHA) . Ninenty (90) researchers from 22 countries participated onsite at the final conference. The goal of the conference was to discuss and present the results of the research of the four-year Action in the field of neutropenias - in children and adults alike - the prevention of its progression into acute leukemia , to highlight the recent focus areas which have emerged and the prospects of continuing the existing collaborations and research between partners of the Action. During the conference, young investigators had the opportunity to present their recent results on their work in the field of neutropenias, discuss with experts in the field, expand their scientific network and promote further collaborations between research Institutions and hospitals across Europe. The EuNet-INNOCHRON Action developed into a very successful network and interactive community , thanks to a number of dedicated scientists who looked into detail into current and future aspects of neutropenia, enhancing collaborations. Of equal significance, is the opportunity offered to many young clinicians and researchers across the EU including inclusiveness target countries and near neighbor countries to train in the field of neutropenias, a rare-disease condition which often leads to pre-leukemia. Highlights Prof. Helen Papadaki Particularly important is the Common EU Guidelines on the diagnosis and Management of Neutropenia jointly published by EUNET-INNOCHRON and the European Hematology Association, for the benefit of patients, their families and caretakers and practicing clinicians. This publication focuses on neutropenia overall, and only touches on SDS superficially. However, it encourages genetic testing to include SDS and other genetic causes of neutropenia and references other important articles. Patient representatives were also present and provided their perspectives, helping redefine therapeutic goals while providing insights on their expectations. Thanks to the network’s work, patients have a better chance of receiving proper treatment in their place of residence. Furthermore, we have at our fingertips big data and to harvest information critical to define treatments including molecular structure of the disease, biomarkers and other parameters which aid in the prevention, diagnosis and proper monitoring of the patients’ condition. - Dr. Papadaki concludes On behalf of the SDS patient and advocacy community, the SDS Alliance would like to express our sincere gratitude for the opportunity to participate in this important action, community, and meeting. 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: New research genetic testing opportunity for individuals suspected to have 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! SDS Alliance Announces Collaboration with Rare Genomes Project Timely and accurate diagnosis of Shwachman-Diamond Syndrome (SDS) is critical for patients to access optimal care, education, and community support. We are excited to announce our new collaboration with the Rare Genomes Project (RGP)  at the Broad Institute of MIT and Harvard. The RGP is a free and remote research program using genomic sequencing to look for the genetic cause of rare diseases, such as SDS. Eligible families will be asked to provide a blood sample and medical information. If a result is found, the RGP team will work with your doctor to confirm the result. What is the purpose of this study? The Rare Genomes Project is a research study focused on patients and families with rare and genetically undiagnosed conditions, now including those suspected to have SDS. The RGP uses genomic sequencing to search for the cause of rare disease in these families and hopes to accelerate the rate of rare disease diagnosis in the process.  How is the genetic sequencing done? What is particularly exciting about this project is that it uses Whole Genome Sequencing (WGS), sequencing the entire genome, not "just" the coding sequences called as genes (as in Whole Exome Sequencing (WES)) but also everything in between. Are you curious how WGS is done? Check out this short video overview, below. For more details about the difference between WGS and WES, check out this video . Who is eligible to participate in our new collaboration? Those who have a clinical suspicion for SDS, including a history of two or more of the symptoms listed below . (“A history of'' means that these symptoms may have happened in the past and resolved by the time participation in the RGP is considered.) Exocrine pancreatic insufficiency (EPI): Decreased pancreatic enzymes (serum trypsinogen or pancreatic isoamylase), decreased fecal elastase, malabsorption, or steatorrhea Hematologic abnormalities: Cytopenias including neutropenia, hypocellular bone marrow, bone marrow failure, or MDS/AML Skeletal dysplasia: Rib cage/thoracic abnormality, metaphyseal dysostosis, extremity abnormalities, scoliosis, or abnormal bone density Individuals with a suspected genetic cause that has not been identified due to prior testing being negative or inconclusive OR a lack of access to genetic testing . ( This means that patients who have received genetic testing previously ARE eligible to participate, as long as prior testing has not yielded a diagnosis.) Applicants for the RGP must live in the United States . How do I get involved? Participation is initiated by eligible patients and families by completing an online application which asks questions about personal and family medical history. The RGP research team will review your application to determine eligibility - this application review process may include a request for additional medical records. Eligible families will also be invited to participate in a virtual introductory meeting to meet the RGP team and discuss participation details such as submitting a blood sample. For more information, you can watch the video below or visit this webpage on the RGP website . Will I receive genetic testing results? The goal of the RGP-SDSA collaboration is to find the genetic explanation for SDS in each family who enrolls, but the RGP cannot guarantee that they will have a result for each family. Because this is research-based genetic testing, the process is expected to take longer than routine genetic testing. If the RGP finds a genetic variant(s) that may explain SDS in the family member with the condition, the RGP team will work with affected individuals to clinically confirm and return the results. The RGP does not return results to unaffected family members. How will I receive genetic testing results? If the RGP finds results that they believe explains the underlying cause of SDS present in your family, they will contact you and ask if you would like to have the findings clinically confirmed in a CLIA-certified laboratory. A genetic counselor on the RGP staff will work with a doctor of your choice to order testing through the CLIA-certified lab. The doctor who orders the clinical test will be the one who shares the results with you. If this project sounds like it could benefit you or a loved one, we encourage you to fill out an application on the RGP website . More resources The SDS Alliance team is available for guidance at connect@SDSAlliance.org .   At SDS Alliance, we have assembled resources for possible patients and their healthcare providers to access no-cost testing options, wherever you are. This page is dedicated to the SDSA partnership with the Rare Genomes Project  to provide access to whole-genome sequencing on a research basis to US residents. If this program doesn't work for you, please check out our other resources or email us at connect@SDSAlliance.org .   Download a printable flyer here, available in English and Spanish: 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: Dr. Alan Warren's group reviews cutting edge research on clonal hematopoiesis and its impact on personalized medicine opportunities for 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! Understanding the Role of Blood and Bone Marrow Stem Cell Mutations and Their Impact on SDS Progression and Treatment Shwachman-Diamond Syndrome (SDS) is a rare genetic disorder that affects the bone marrow, pancreas, and skeletal system. Recently, researchers have made significant strides in understanding how somatic (or acquired) genetic mutations play a role in the bone marrow failure of patients with SDS. Dr. Alan Warren and his team recently published a review of these advancements in Blood , the official journal of the American Society of Hematology.  One study highlighted in this review  used advanced techniques to map relationships between the blood and bone marrow stem cells in patients with SDS, shedding light on the mutations that may influence the development and progression of MDS and AML. This was done by analyzing individual stem cells from the blood and bone marrow of ten SDS patients aged 4 to 33 years. Researchers discovered that most of these patients had large groups of bone marrow stem cells with a lot of somatic (or acquired) genetic mutations, such as mutations in the TP53 gene, a pattern usually seen in much older individuals. This suggests that blood and bone marrow stem cells in SDS patients are affected early in life, contributing to the development of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) at younger ages.  Another recent finding highlighted by this review, was the role of acquired (somatic) mutations and how the different somatic mutations interact. While acquired (somatic) mutations were common in the blood and bone marrow stem cells of patients with SDS, not all somatic mutations led to severe consequences. Interestingly, some somatic mutations seemed to help cells survive better despite the SDS-related defects. These "rescue" mutations potentially lower the risk of disease progression to MDS or AML. However, when acquired TP53 mutations occur in both copies of the gene, it can lead to severe conditions like MDS or AML. For more information regarding the development of clones and the difference between somatic and germline variants, watch the video below or review these previously published SDS & Science Snapshots ( Somatic and Germline Variants  or The Difference between Germline and Somatic Genetic Testing ). The review published by Dr. Warren and his team shared that multiple recent studies have had similar findings, reporting that up to 72% of SDS patients often develop clonal hematopoiesis (CH). CH happens when some blood and bone marrow stem cells with specific “signatures” of acquired (or somatic) mutations start to dominate, but other features of MDS and AML are not present in the bone marrow. The acquired CH mutations observed in SDS patients were usually different from those seen in older adults without SDS. By tracking these mutations over time, researchers hope to better understand how they affect disease progression from CH to MDS and AML. For more information about clones, how they develop, and how to monitor the development of them, watch the video below. Dr. Warren and his team emphasized the timing of when these somatic mutations occur is also crucial. By building a "family tree" of stem cell mutations, researchers can estimate when specific mutations happened. Some mutations in SDS patients can occur very early, even before birth. Following the “family tree” of somatic mutations and how they relate to early somatic mutations highlights the importance of monitoring SDS patients from a young age. Dr. Warren presented part of this work and background virtually as part of the 2024 Expert Webinar Series, hosted by our Australian partner organization, Maddie Riewoldt's Vision , focused on funding research to discover cures for Bone Marrow Failure Syndromes. For families and patients with SDS, these findings emphasize the importance of regular bone marrow biopsies and somatic genomic testing (also known as NGS)  on these bone marrow biopsy samples and/or on peripheral blood samples. Understanding which somatic mutations are present in the blood and bone marrow of SDS patients can help doctors predict the risk of disease progression and make informed decisions about treatments, including the potential of bone marrow transplant. As research advances, it may also lead to new therapies that target specific somatic mutations or pathways, offering hope for better outcomes in the future. Cull AH, Kent DG, Warren AJ. Emerging genetic technologies informing personalized medicine in SDS and other inherited bone marrow failure disorders. Blood. 2024 Jun 21:blood.2023019986. Epub ahead of print. PMID: 38905596 . 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: New research with induced pluripotent stem cells is shedding new light on our understanding of 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! Unlocking the Secrets of Early Development in SDS with Induced Pluripotent Stem Cells Shwachman-Diamond syndrome (SDS) is a rare genetic disorder that affects the bone marrow, leading to a shortage of blood cells. It can also cause other problems in the body and increase the risk of leukemia, a type of cancer. The disorder is mainly caused by mutations in the SBDS gene, which is important for making ribosomes, the cell’s protein factories. Without proper SBDS function, not enough ribosomes can form, leading to many of the issues seen in SDS. In the SDS & Science Snapshot this week, we are highlighting a recent study led and published by Dr. Yigal Dror , a leading physician-researcher on inherited bone marrow failure syndromes from The Hospital for Sick Children (SickKids in Toronto). In this study, Dr. Dror and his research team wanted to find out exactly when the blood cell problems of individuals with SDS begin during development with the hopes of guiding future research in therapy development. To do this, Dr. Dror and his research team created a special type of cell called induced pluripotent stem cells (iPSCs) using cells from bone marrow samples from SDS patients and healthy controls, which can turn into any cell type in the body. This ability to “shape shift” makes iPSCs a powerful tool for studying early embryonic development, as they can be used to observe how diseases or genetic conditions affect the formation of different cell types from the very beginning. Additionally, iPSCs can be used to model diseases in the lab, allowing scientists to explore new treatments and understand the underlying mechanisms of various disorders without the need for embryonic stem cells. For more information about the important use of iPSCs in research, you can watch the video below. Key Findings from this Study: Lower Efficiency in Cell Reprogramming : The researchers found that it was much harder to create iPSCs from SDS patients compared to heathy donors, suggesting that cells from SDS patients are either less fit or have a reduced ability to be reprogrammed into stem cells. Defects in Blood Cell Formation : When the iPSCs from SDS patients were encouraged to become blood cells, they formed far fewer blood cells than the healthy iPSCs. This means that the blood cells in SDS patients have trouble developing properly, which can explain the issues with healthy blood cell development (like neutropenia) seen in SDS patients. Early Developmental Issues : The study also showed that the problems start at a specific stage of blood cell development, known as the early emerging hematopoietic progenitors (EHPs) stage. This is an early step in the process where stem cells start to become specialized blood cells. SDS cells had fewer EHPs, and these cells were less able to grow and multiply. Potential for New Treatments:  One exciting aspect of this study is that the researchers found that adding back the SBDS gene to the SDS iPSCs improved their ability to form blood cells. This suggests that gene therapy, which aims to correct the defective gene, might be a promising treatment for SDS. Additionally, understanding the specific stages and processes affected by SDS helps in designing drugs that can target these problems more precisely, and provides a rationale to apply treatments as early in life as possible. Mapping Gene Pathways in SDS: Lastly, the researchers in this study investigated the gene expression during early development of these iPSCs from SDS patients. By analyzing these iPSCs, they identified important genes and cellular pathways that are activated or repressed at various stages of cell development. This detailed mapping of gene activity may help in understanding the differences between healthy and SDS iPSCs, providing valuable information for developing targeted therapies for SDS. Understanding exactly when and how blood cell problems start in those with SDS can help scientists develop better, more effective treatments. By knowing that the defect begins at the EHP stage, researchers can target this stage to find ways to prevent or correct these defects. These findings could help lay the groundwork for new therapies that can improve blood cell production in SDS patients, reducing the need for frequent treatments and improving quality of life. This also underscores the critical importance of early and accurate diagnosis of SDS, so that any treatment can be started as early in life as possible, when the benefits may be the biggest. With continued research, there is potential for significant improvements in managing and treating SDS! Lagos-Monzon A, Ng S, Luca AM, Li H, Sabanayagam M, Benicio M, Moshiri H, Armstrong R, Tailor C, Kennedy M, Grunebaum E, Keller G, Dror Y. Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman-Diamond syndrome. Eur J Haematol. 2024 Jul 5. PMID: 38967591 . Do you enjoy the SDS & Science Snapshots? 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"We have reached the stage of acceptance and trying to live life the fullest despite SDS" Shares Octavian's dad, Raul. Read this Romanian family's story, here. At the beginning of 2023 we found out with great joy that we will be expecting our second child and we could not be happier knowing that our family will grow. The pregnancy was monitored carefully each trimester and for the first two, it seemed to be all ok, the baby was growing as expected, everything was within normal parameters. That was until one of our check-ups during the 3rd trimester, where after an ultrasound examination, the doctors informed us that it seems that the baby's limbs are not growing in accordance with his gestational age and the doctors were starting to suspect a possible genetic condition (achondroplasia). Of course, we were devastated to even consider that our yet unborn baby boy could be in any way sick, and went through all the possible stages - crying, denial, anger, - you name it... Regardless, there was nothing we could do but wait and see... Finally, October arrived and Octavian was born at the maternity hospital in our city in Romania. His APGAR score was 9, as for the first hours outside the womb, he had some breathing related issues, but thank God, afterwards his breathing got better and did not need to undergo any more oxygen therapy. He was quite small, 46 cm and 2.6 kg but was from the start, very very beautiful. The genetics department from the maternity hospital suggested we should test him for achondroplasia, but as my parents are pediatricians, they both suggested that it makes no sense, because from their experience it was clearly not the case of achondroplasia. They were the ones that encouraged us to go for the Whole Exome Testing and did so in November. For the first 3 months, Octavian was doing quite well, he was eating well (breastfed + extra formula) and was gaining steadily weight at a normal rate. We were very proud of our little man because even when he had the misfortune of contracting pneumonia from his older brother, he still did not lose weight, and was still eating with pleasure. Close to Christmas time, he started eating smaller and smaller portions, and showing signs of abdominal distress, so we tried to switch to any possible formula for the coming period and giving him any possible supplements to help with digestion. Now we entered the stage where he simply stopped gaining weight and was somehow blocked at 3.9 kg for almost 2 months... In the meantime, we got the results back from the Whole Exome Genetic Testing and we celebrated because it clearly stated he has NO achondroplasia. For about 2-3 days we just couldn’t realize that there was something else highlighted in the results: The patient is heterozygous for EFL1 [...], which is a variant of uncertain significance (VUS). The patient is heterozygous for EFL1 [...], which is a variant of uncertain significance (VUS). Biallelic pathogenic variants in EFL1 have been associated with Shwachman-Diamond syndrome 2 (SDS; MIM #617941; GeneReviews NBK1756), an autosomal recessive disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature. At some point, again my parents suggested to test his elastase levels from his stool and we got back two consecutive results for exocrine pancreatic insufficiency ….Now it started to become clear to us that it could be the case that our son has SDS….It came as a shock to us to find out that at our centers for Cystic Fibrosis, the doctors have never seen SDS…We felt pretty much on our own, until one day we went online and found the SDS support group and got in touch with multiple people and patients and were all of the sudden surrounded by information and encouragement from the group. Eszter Hars of the SDS Alliance was one of the people that helped us the most from the community, she helped us get in contact with specialist in Europe that have experience with SDS and in April we were lucky to be accepted for a visit at Dr. Cipolli Marco in Verona Italy. We were happy to be in the hands of specialists that know how to handle Octavian’s condition. A holistic approach of his condition was undertaken in Verona and after careful evaluation, Octavian was confirmed clinically with SDS .  [Editorial comment: due to the mutations being classified as VUS, the patient received his diagnosis by an SDS expert based on clinical (symptom) findings, which is known as a clinical diagnosis as opposed to genetic confirmation. About 10% of SDS patients are diagnosed clinically]. This condition was classified as being mild, showing skeletal abnormalities in the form of a narrow chest and pancreatic insufficiency. His bloodwork is ok, showing no signs of neutropenia or anemia. We came back to Romania with a plan and clear indications on how to administer enzymes to help him digest food and we have scheduled a follow up visit in the coming year. Octavian is now 8 months old. He is still small for his age and is still struggling to reach the milestones that most kids reach by the age of 8 months because of his hypotonia. He is now 60cm tall and weighing 4.6 kg. Despite his condition he is a very happy little man. He smiles all the time, he is very happy to spend time with his older brother and is musically inclined – his face lights up when we put music on.  We have come a long way in just 8 months, 8 months ago we never heard of SDS and never even considered the chance of our child to suffer from a rare disease… We learned in this short period that we are strong together, and that there is a community that we can rely on when in need. We went from being completely lost, to having a plan, and for the first time in our SDS journey I think we have reached as a family the stage of acceptance and trying to live life the fullest despite SDS. [Written and submitted from Octavian's dad, Raul]

In this issue: How do lung microbiomes improve outcomes for bone marrow transplant patients? 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! New Insights into Lung Microbiomes and Bone Marrow Transplant Outcomes When children undergo bone marrow transplant (BMT), such as those with Shwachman-Diamond Syndrome (SDS), even small infections, such as respiratory infections, can become very dangerous. A team of scientists around the world recently published a new method to quickly identify all the microscopic organisms in the lungs of these children after BMT with the hopes of improving transplant outcomes. This collection of microscopic organisms, referred to as the microbiome, includes bacteria, viruses, fungi, and other microbes, that live all over our bodies, including inside the lungs. Just like the gut microbiome, the lung microbiome plays a crucial role in maintaining health and protecting against infections. A balanced lung microbiome helps the immune system function properly, whereas an imbalance can make individuals more susceptible to diseases and infections. The researchers of this study discovered that certain groups of microbes in the lungs can predict which patients after BMT are at higher risk of dying from lung infections. The video below explores the origin, purpose, and importance of the human microbiome. Researchers in this new study used a technique called metagenomic next-generation sequencing (mNGS) to examine the microbiome of lung fluid from many pediatric patients after BMT. This method allowed the researchers to find and categorize all the microbes in the samples. Importantly, these researchers identified four different groups of patients based on the types and amounts of microbes in their lungs, helping them predict which children were more likely to suffer severe lung injuries, including lung infections. Bone marrow transplants can be life-saving interventions for children with leukemia, bone marrow failure, and genetic disorders like SDS. However, the process of BMT involves strong chemotherapy that weakens the immune system and makes these individuals highly susceptible to infections. Unfortunately, these infections can be deadly, especially when patients need ventilators. Traditional tests may miss some pathogens (like bacteria and viruses) that cause these infections after BMT, but mNGS can identify a wide range of microscopic organisms, including rare ones, enabling more accurate treatments and improve outcomes. By analyzing the mNGS data of these microscopic organisms in the lung microbiome of bone marrow transplant patients, the researchers discovered that patients in the group with the highest risk of death after bone marrow transplant not only had fewer types of microbes in their microbiome, but also had more Staphylococcus bacteria and viruses. This research suggests that a balanced lung microbiome is crucial for better bone marrow transplant outcomes. For children with Shwachman-Diamond Syndrome (SDS), who are prone to infections and often need bone marrow transplants, these findings are especially important. Understanding the lung microbiome could help doctors better predict and treat infections in these patients. Using mNGS could lead to more precise treatments, improving survival rates for SDS patients undergoing transplants by allowing doctors to quickly identify and address the specific microbes causing infections after bone marrow transplant. The SDS & Science Snapshot this week contains content modified from materials in this blog post, Lung Microbiomes Predict Mortality in Children Following Bone Marrow Transplant, published the Chan Zuckerburg Biohub Network. Zinter MS, Dvorak CC, Mayday MY, Reyes G, Simon MR, Pearce EM, Kim H, Shaw PJ, Rowan CM, Auletta JJ, Martin PL, Godder K, Duncan CN, Lalefar NR, Kreml EM, Hume JR, Abdel-Azim H, Hurley C, Cuvelier GDE, Keating AK, Qayed M, Killinger JS, Fitzgerald JC, Hanna R, Mahadeo KM, Quigg TC, Satwani P, Castillo P, Gertz SJ, Moore TB, Hanisch B, Abdel-Mageed A, Phelan R, Davis DB, Hudspeth MP, Yanik GA, Pulsipher MA, Sulaiman I, Segal LN, Versluys BA, Lindemans CA, Boelens JJ, DeRisi JL. Pediatric Transplantation and Cell Therapy Consortium. Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation. Nat Med. 2024 May 23. PMID: 38783139. 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 is the difference between germline and somatic genetic testing? 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! Ask an Expert Recap: The Difference between Germline and Somatic Genetic Testing At the most recent Ask an Expert webinar in May (see below), we heard from Dr. Lisa J. McReynolds, one of the newest members of the SDS Alliance Medical and Scientific Advisory Board (you can read her biography and more about her work here and welcome to the SDS Alliance community, Dr. McReynolds!). In this meeting, one of the topics discussed was the importance of diagnostic genetic testing for individuals with SDS and how hereditary (germline) variants (or mutations) are different from somatic mutations detected in cancerous (or pre-cancerous) cells, also known as clones. In our SDS & Science Snapshot this week, we will discuss the difference between these two mutation types (and how they are tested for) in more detail. In the world of cancer, there are two main types of genetic tests that are used to inform care: germline genetic testing and somatic tumor (genomic) testing. Understanding the difference between these two types of mutations can be helpful in navigating the complexities of SDS. In a previous SDS & Science Snapshot, we discussed the difference between germline and somatic variants (or mutations). The figure below compares germline genetic testing and somatic genomic tumor testing. Sometimes in the clinic, somatic genomic tumor testing is also referred to as “NGS” (which stands for “next-generation sequencing”) and is frequently performed on the bone marrow biopsy samples from patients with SDS as discussed below. While the results of these two types of genetic testing often look similar, there are a few key differences in the somatic genomic tumor testing to look out for: Variant allele frequency (VAF): This is how often the variant (or variants) were seen in the tested sample of cancerous (or pre-cancerous) cells. VAF provides insights to how predominant the variant (or variants) may be in the tumor sample. Knowing the VAF of somatic variants detected in a bone marrow biopsy sample can help your care team monitor for the development of MDS or AML or give insight into how someone with MDS or AML is responding to treatment. Key difference: Sometimes germline variants can be identified on somatic genomic testing, but the VAF of germline genetic variants is typically around 50% and, if detected, are generally expected to remain constant across multiple somatic genomic tests. This is in comparison to the VAFs of somatic mutations, which change over time as the clones of cancerous cells develop and evolve over time. Genes: Some genes are more commonly altered in pre-cancerous or cancerous cells than others. For example, TP53 variants are frequently seen in the bone marrow samples of individuals with MDS or AML, but most of those individuals do not have a germline TP53 variant, or Li Fraumeni Syndrome. Other examples of genes commonly mutated in the bone marrow samples of individuals with MDS or AML include DNMT3A, TET2, CSF3R, SF3B1, IDH1/2, RUNX1, and GATA2. Report Comments: Somatic genomic tumor testing (or NGS) are not meant to detect germline variants. If there is concern for the accidental detection of a germline variant that may play a role in a patient’s care plan, there will often be a comment about this in the NGS report. For more information regarding the development of clones and the difference between somatic and germline variants, you can watch this educational video on the genetics of SDS. We cover the concept of germline versus somatic variants (around minute 5), and how they relate to leukemia. You might also find it helpful to watch the recording of the Ask an Expert webinar with Dr. Lisa J. McReynolds above. We encourage you to ask your healthcare provider about any questions you have about any genetic testing results, germline or somatic, and how these are used to manage care. For more information regarding the difference between somatic and germline variants, you can visit the Cleveland Clinic’s website. The SDS & Science Snapshot this week contains content modified from materials in this blog post, Tumor Genetics: Somatic vs Hereditary, published by Quest Diagnostics. 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: Is a new screening test for SDS on the horizon? 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! New Publication Combines Protein and Genetic Analyses to Help Diagnose Individuals with SDS The process of identifying the genetic mutations responsible for an individual's diagnosis of Shwachman-Diamond Syndrome (SDS) can be complex, time-consuming, difficult to access, and expensive, especially when genetic tests don’t find the typical mutations. This is where exciting new fields called proteomics and proteogenomics can be helpful! In this SDS & Science Snapshot, we will highlight a new publication of a proteogenomic study in individuals with SDS and other inherited bone marrow failure syndromes which may help establish a new faster and cheaper way to screen for SDS before (or after) completing genetic testing! Proteomics is the study of proteins in our bodies. Proteins are like tiny machines that do all sorts of important jobs, like building tissues and fighting off infections. By looking at the quantity and quality of all the proteins in a person’s cells, scientists can uncover differences in proteins that are responsible for disease (and might also help provide hints as to what genes to analyze in genetic testing). Proteogenomics combines proteomics with genomics, the study of genes. This means scientists look at both the genes and the proteins to get a complete picture of what’s happening at the cellular level. The video below published by the National Cancer Institute describes proteomics and proteogenomics and how these methods may be particularly helpful in treating cancer, but the same concepts can generally apply to SDS as well. For people with SDS, proteomics and proteogenomics could be very useful. Even if a genetic test doesn’t show the usual SDS mutations, these new technologies can look at a different angle to help find changes in protein levels or protein interactions, which might reveal hidden problems that genetic tests miss. For example, if a person with SDS has unusual protein patterns, doctors might be able to spot this and diagnose SDS earlier. Since genetic testing is frequently complicated by the SBDS pseudogene (as reviewed in this previous SDS & Science Snapshot), these new types of analyses for individuals with mutations in the SBDS gene may be especially helpful in serving as a screening mechanism, signaling to a patient’s care team to keep searching for genetic mutations. Using samples from individuals with inherited bone marrow syndromes, including SDS, researchers from Japan were able to test a new type of proteogenomic analysis to help screen for individuals with SDS based on the amount of SBDS protein in a patient's cells. These researchers found that individuals with low amounts of SBDS protein in blood also had mutations in the SBDS gene as revealed by genetic testing. By combining proteomics and genomics, some abnormal results in this study also helped lead researchers to using a different type of genetic testing to definitively identify SBDS mutations and provide a SDS diagnosis for two patients! To the best of our knowledge, this was the first time that a simple, rapid screening test has been developed for diagnosing SDS. The authors suggest this type of proteomic-based diagnostic pathway could be easily and rapidly used across a large number of samples, leading to early identification of SDS and therapeutic intervention. These findings are encouraging and important for reducing the burden of the diagnostic odyssey for individuals with SDS. More research is still required to validate these types of proteomic and proteogenomic diagnostic methods, especially for those with genetic mutations in more rare SDS genes such as DNAJC21, EFL1, and SRP54. Wakamatsu M, Muramatsu H, Sato H, Ishikawa M, Konno R, Nakajima D, Hamada M, Okuno Y, Kawashima Y, Hama A, Ito M, Iwafuchi H, Takahashi Y, Ohara O. Integrated proteogenomic analysis for inherited bone marrow failure syndrome. Leukemia. 2024 May 13. doi: 10.1038/s41375-024-02263-1. Epub ahead of print. PMID: 38740980. 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: SDS identified as a common cause of inherited neutropenia in the Israeli Inherited Bone Marrow Failure Registry! 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! The Genetic Landscape of Inherited Neutropenia in the Israeli Inherited Bone Marrow Failure Registry In a study recently published in April, researchers investigated the genetic landscape of inherited neutropenia within the Israeli population. As many individuals in the Shwachman-Diamond Syndrome (SDS) community are familiar, neutropenia is characterized by abnormally low levels of neutrophils (a type of white blood cell which plays an important role in the immune system) and can leave individuals vulnerable to recurrent infections and other health complications. This new study, conducted with participants from the Israeli Inherited Bone Marrow Failure Registry, shed light on the genetic cause of inherited neutropenia in Israel, offering hope for improved diagnosis and management strategies. Out of the 65 individuals with inherited neutropenia enrolled in the Israeli Inherited Bone Marrow Failure Registry, 74% received a genetic diagnosis. As pictured below, the most common forms of inherited neutropenia identified were ELANE neutropenia and G6PC3-severe congenital neutropenia. Interestingly, diagnoses of SDS and SDS-like syndromes were the third and fourth most common cause of inherited neutropenia in the Israeli Inherited Bone Marrow Failure Syndrome study with more than 25% of individuals having variants identified in the SBDS and SRP54 genes. Among those with positive genetic testing, 15% had two mutations (or variants) detected in the SBDS gene. These individuals, primarily of Jewish or Arab Muslim descent, presented with a spectrum of common SDS symptoms, including pancreatic insufficiency, severe infections, and skeletal abnormalities. Interestingly, around 12% of individuals with positive genetic testing had one mutation identified in the SRP54 gene, reported to cause an SDS-like syndrome. These individuals (even individuals within the same family) displayed a range of symptoms, including a few with mild, resolving exocrine pancreatic insufficiency and failure to thrive, reminiscent of SDS caused by SBDS mutations. When we reached out to Dr. Steinberg-Shemer, she highlighted that patients with SRP54 in Israel actually had isolated neutropenia with no significant pancreatic insufficiency. For more information about the symptoms and genetic cause of SDS, you can watch the video below. Importantly, the study reported that while none of the participants with SDS or SDS-like syndromes had been diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), one individual successfully underwent a bone marrow transplant due to bone marrow failure. However, the authors of this study emphasized the importance of participating in regular bone marrow surveillance for those with SDS diagnoses. These findings show the importance of participating in genetic testing for individuals with chronic neutropenia and frequent infections, especially for those at a young age. By identifying the genetic cause behind inherited neutropenia conditions, healthcare teams can tailor disease management strategies such as regular bone marrow surveillance for those with SDS. As we were reminded in last week’s SDS & Science Snapshot, understanding the genetic landscape of SDS and SDS-like syndromes in diverse populations, like in this Israeli cohort, is crucial for advocating for improved treatments and outcomes for individuals with SDS and SDS-like syndromes worldwide. For more information regarding the clinical presentation of SDS and flyers about SDS to share with your care team, you can visit our “What is SDS?” page. Disclaimer: The information contained in this blog post is an overview of published research and is not intended to be medical advice. If you are concerned you, or a loved one, has SDS, please contact your healthcare team. Yeshareem L, Yacobovich J, Lebel A, Noy-Lotan S, Dgany O, Krasnov T, Berger Pinto G, Oniashvili N, Mardoukh J, Bielorai B, Laor R, Mandel-Shorer N, Ben Barak A, Levin C, Asleh M, Miskin H, Revel-Vilk S, Levin D, Benish M, Zuckerman T, Wolach O, Pazgal I, Brik Simon D, Gilad O, Yanir AD, Goldberg TA, Izraeli S, Tamary H, Steinberg-Shemer O. Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel. Eur J Haematol. 2024 Apr 11. doi: 10.1111/ejh.14197. Epub ahead of print. PMID: 38600884. 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: A new publication describing the symptoms of SDS in patients in China! 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! New Publication Highlights the Symptoms of SDS in China In April, a new scientific article was published reviewing the symptoms of Shwachman-Diamond Syndrome (SDS) within the Chinese population, shedding light on this rare disease. As you may know, SDS is characterized by various symptoms like low blood cell counts, gastrointestinal problems (for example, chronic diarrhea/steatorrhea as a result of pancreatic insufficiency), developmental delays, skeletal abnormalities, and frequent infections. With this in mind, the authors of this publication found that SDS presents similarly in individuals from China as in other parts of the world. Not uncommon to the rare disease community, this study also found that about half of those with SDS faced delays in diagnosis (more than 2 years!), showing a need for greater awareness among healthcare providers, especially pediatricians in China. This publication revealed that the most common symptoms at diagnosis in individuals with SDS in China included low blood counts (also known as cytopenia) and chronic diarrhea, while other issues like short stature and skeletal abnormalities were also common. Interestingly, while the gastrointestinal symptoms of pancreatic insufficiency tended to improve over time, low blood cell counts continued over time, which aligns with existing knowledge about the symptoms of SDS. The authors of this article also reviewed the genetic testing results of individuals with SDS in China and they found most individuals with SDS carried the two most common variants mutations (or variants) in the SBDS gene (c.258+2T>C and c.183_184TA>CT) with other genetic mutations in the SBDS gene being more rare. Interestingly, there was one report of an individual with a mutation in the SRP54, which causes a so-called SDS-like syndrome and is inherited in an autosomal dominant pattern. For more information about the symptoms and genetic cause of SDS, check out the video below. Moving forward, the authors of this publication advocate for a collaborative approach to managing SDS (as discussed in this previous SDS & Science Snapshot and pictured below), emphasizing the need for early diagnosis and proactive monitoring for potential complications like MDS and AML. Interestingly, MDS and AML were rarely reported in the Chinese SDS community, but the authors suggested this was because of a general lack of understanding and awareness about SDS amongst healthcare providers in China (one case report of an individual with SDS and AML in China was recently reviewed in this SDS & Science Snapshot). This publication holds particular significance as it coincides with Asian American and Pacific Islander Heritage Month in the United States and serves as a reminder of the importance of understanding and advocating for individuals with SDS all over the world. At SDS Alliance, we recognize that our community is diverse, and we are committed to engaging with our global community to accelerate progress towards improved treatments and outcomes with SDS across the world. For more information regarding the clinical presentation of SDS and flyers about SDS to share with your care team, you can visit our “What is SDS?” page. Disclaimer: The information contained in this blog post is an overview of published research and is not intended to be medical advice. If you are concerned you, or a loved one, has SDS, please contact your healthcare team. Clinical and genetic characteristics of Chinese patients with Shwachman Diamond syndrome: a literature review of Chinese publication. Wang L, Jin Y, Chen Y, Zhao P, Shang X, Liu H, Sun L. Exp Biol Med (Maywood). 2024 Apr 8;249:10035. doi: 10.3389/ebm.2024.10035. PMID: 38651168. 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: New study publishes growth charts custom for individuals with 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! New Study Publishes Custom Growth Charts for Individuals with SDS from Childhood to Adulthood You've probably seen growth charts at the doctor's office or in a medical record — they track how kids grow over time, comparing their height and weight to others their age. But for some, like those with Shwachman-Diamond Syndrome (SDS), those charts might not tell the whole story. As we know, SDS is a complex disorder affecting many systems. The majority of individuals with SDS have some degree of exocrine pancreatic insufficiency. This can lead to problems with digesting food and getting the right nutrients, which can cause them not to grow as much as other kids. Other common symptoms of SDS include failure to thrive and skeletal abnormalities, which also impact an individual’s growth and development compared to someone without SDS. So, using regular growth charts can be misleading for someone with SDS because their growth might not match what's expected for their age group. That's why custom (or disease/population specific) growth charts are so important for people with SDS. These growth charts are made just for them, considering their unique needs and challenges. Unlike regular growth charts, which might suggest they're not growing well, personalized growth charts give a clearer picture of how they're doing. Until recently, custom growth charts were only available to individuals with SDS from 0 to 8 years of age. earlier this month, researchers in Italy published custom growth charts created for individuals with SDS from 0 to 18 years of age! These growth charts (pictured below) for height (a-b), weight (c-d), and BMI (e-f) were created from a large cohort of 121 individuals with SDS and over 700 growth measurements for both males (left panel) and females (right panel). Growth charts for males (left) and females (right) with SDS for height (a-b), weight (c-d), and body mass index (BMI; e-f) of patients with SDS from ages 0 to 18 years. These researchers found that the 50th and 3rd percentiles of weight and height of the pediatric general population corresponds to the 97th and 50th percentiles of patients with SDS aged 0-18 years, respectively. In other words, if a child with SDS weighs in at about the 3rd percentile on the generic growth chart, that would correspond to the 50th percentile on the SDS growth chart. This could then be interpreted as the child doing well, right on target/average in terms of their weight compared to other children who also have SDS. Of course, families are encouraged to discuss such interpretations and all treatments with their health care team. This finding is an example of how using regular growth charts can be misleading for someone with SDS because their growth might not match what's expected for their age group. Personalized growth charts for SDS not only help you to understand how individuals with SDS are growing, but it can also help doctors track how well treatments are working. For example, if someone with SDS tries a new medicine or therapy, this growth chart for individuals with SDS can show if it's helping them grow stronger and healthier. These growth charts also help families understand their child's growth better, from 0 to 18 years. Instead of feeling confused by the numbers, you can see how your loved one is doing compared to others with SDS. This can help you feel more confident in managing your loved one’s health and making decisions about their care. We encourage you to share this publication and these growth charts with your healthcare team to see how they can help you in your journey with SDS! Pegoraro A, Bezzerri V, Tridello G, Brignole C, Lucca F, Pintani E, Danesino C, Cesaro S, Fioredda F, Cipolli M. Growth Charts for Shwachman-Diamond Syndrome at Ages 0 to 18 Years. Cancers (Basel). 2024 Apr 5;16(7):1420. doi: 10.3390/cancers16071420. PMID: 38611098. 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: New research opportunity for siblings to individuals with 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! An exploration of the experiences of siblings of people with a diagnosis of Shwachman-Diamond Syndrome Living with a sibling who has a rare disease like Shwachman-Diamond Syndrome (SDS) can be a complex experience for the unaffected sibling(s). While they may not have the same physical symptoms or medical needs, the emotional impact can be significant and often introduce unique challenges to the family dynamic. Despite not having SDS themselves, the unaffected sibling's life is inevitably shaped by its presence, leading to a complex mix of emotions that require understanding and support from those around them. Other studies investigating the experience of siblings to individuals with inherited bone marrow failure syndromes such as Fanconi anemia have been published, but the experience of unaffected siblings to those with SDS have not been specifically explored… until now! In our SDS & Science Snapshot this week, we are happy to share a new research opportunity exploring the experiences of siblings to individuals with SDS. This study is being led by Amy Doyle, a family therapy trainee at the University of Exeter in England, United Kingdom. Here is what Amy, the lead researcher, shared about the importance of this study and how to get involved: What is the purpose of this study? The aim for this study is to learn more about the experiences of siblings to individuals with SDS from childhood to adulthood and to highlight the potential value in and usefulness of additional support such as therapy for families of people experiencing SDS. What is your inspiration for leading this study? I have an interest in and awareness of SDS due to a personal, family connection. In reviewing the current research and learning more about other chronic illnesses, I have recognized that the majority of support that is currently available is for affected individuals. I recognize and am learning that conditions like SDS have an impact on the whole family system and hope that this study can provide insight on this experience. Who is eligible to participate? Individuals who meet the following criteria are eligible to participate: Siblings to individuals with a diagnosis of SDS Adult participants at least 18 years of age Must be able to speak English Access to a computer, internet, and video-conferencing How is this study being conducted? Participants will be asked to answer a brief demographic survey online with questions about age, gender, ethnicity, geographical location, and education level. Following this survey, the lead researcher will conduct individual interviews online via Microsoft Teams. It is anticipated that the interviews will take no longer than one hour. These interviews will be recorded and transcribed by the lead researcher. The interview transcripts will be anonymised and analyzed. What kind of questions will be asked? Questions asked of participants will be particularly centered around individuals’ experiences as siblings, and to explore the impact that SDS has had on their lives as individuals and as a family. Questions will also consider the support that has been offered and is available, as well as what may or may not have been helpful for them and their families. What will happen to the results of this research study? The results of this research study will be analyzed and written up as part of the lead researcher’s final dissertation project. The lead researcher hopes to present the results of this study to the trustees of the Shwachman-Diamond Syndrome UK charity and potentially publish the results in a relevant journal. Who is overseeing this research? This research is being conducted as part of the lead researcher’s final dissertation at the University of Exeter. The researcher’s tutor Kate Campbell is overseeing the research. The Data Controller for this research is the University of Exeter. Ethical approval for this research has been granted by the University of Exeter’s CEDAR psychology ethics committee. How do I get involved? If you are eligible or know someone who is, please don't hesitate to get in touch with me by emailing me at ad903@exeter.ac.uk. I can share my participant information sheet with you and answer any questions that you have. Resources for Siblings to Individuals with a Rare Disease: The Sibling Support Project: https://siblingsupport.org/ Sibling Leadership Network: https://siblingleadership.org/ Rare Sibling Stories: https://linktr.ee/raresiblingstories Stay tuned to our SDS & Science Snapshot series next week to learn more about a new study which published growth charts specific for individuals with SDS! Do you enjoy the SDS & Science Snapshots? You can Sign up by using the button on the top right of this post: