Undiagnosed Diseases Program

未确诊疾病计划

基本信息

批准号：
10939173
负责人：
William Gahl
金额：
$ 24.11万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10939173
关键词：
11 year old 13 year old 14 year old 18 year old 2 year old 20 year old 3 year old 5 year old 6 year old 8 year old Accounting Acidosis Actins Address Adult Affect African Albania Alleles American Apical Apraxias Artificial Intelligence Atypical Mycobacteria Automobile Driving Award Binding Sites Bioinformatics Brain Budgets CCM1 gene Caspase Cells Cerebellar Ataxia Child Childhood Clinical Collaborations Communication Communities Complex Country Cranial Nerves Databases Developing Countries Development Developmental Delay Disorders Developmental apraxia Diagnosis Diagnostic Disease Doctor of Philosophy Encephalopathies Ensure Family Fanconi Syndrome Female Fostering Fracture Funding GTP Binding Gait Genes Genetic Genetic Transcription Genome Genome Stability Genomics Glean Gliomatosis cerebri Goals Growth Histidine-Specific tRNA Human Human Biology Human Genetics Immunology Impairment Improve Access Inflammation Innovative Therapy Inorganic Phosphate Transporter Intellectual functioning disability Interleukin-6 International Intramural Research Journals KBG syndrome Kidney Kidney Failure Knowledge Language Delays Liver Failure Machine Learning Medical Medicine Methodology Minority Groups Mitochondrial Diseases Molecular Molecular Genetics Morphea Movement Mus Muscle Muscle hypotonia Mutation Myopathy National Heart, Lung, and Blood Institute National Human Genome Research Institute National Institute of Allergy and Infectious Disease National Institute of Child Health and Human Development National Institute of Dental and Craniofacial Research National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Mental Health National Institute of Neurological Disorders and Stroke Neuhauser syndrome Neurologist Neurology Neurons New England Nigeria Nuclear Organelles Paper Parkinsonian Disorders Pathogenicity Patients Peripheral Nervous System Diseases Phenotype Physicians Pituitary Gland Postbaccalaureate Process Program Reviews Protein Deficiency Publications Publishing RNA Splicing Rare Diseases Reporting Research Research Personnel Resources Rickets Running SETX gene STAT4 gene Schools Science Scientist Seizures Selenium Skeleton Small Nuclear RNA Speech Spinocerebellar Ataxias Stereotyping Stroke Stroke prevention Support System Surface Syndrome TNF gene Taxes Techniques Technology Toes Topoisomerase III Training Training Programs Tubular formation Tubulin Underserved Population United States National Institutes of Health Variant Writing absorption adenosine deaminase autoinflammatory diseases autosome base boys calcification cerebral cavernous malformations clinical center de novo mutation design diagnostic tool experience gain of function genetic variant girls graduate student health disparity hearing impairment heteroplasmy hexokinase improved innovative technologies inorganic phosphate insight interdisciplinary collaboration interest lectures loss of function male member motor impairment myocyte-specific enhancer-binding-factor 2C neurodevelopment neuroimaging older men older women polyglucosan prevent programs protein complex quadriceps muscle skeletal skills spasticity symposium transcription factor translational research program

项目摘要

FY23 was the first year in which the NIH Undiagnosed Diseases Program operated under funding from the school tax, i.e., the same group of NIH Institutes and Centers that support the NIH Clinical Center based upon the size of their intramural research budgets. For the previous 10 years (2013-2022), the UDP was funded by the Common Fund. William Gahl, MD, PhD, and Adams, MD, PhD, co-direct the UDP; Cynthia Tifft, MD, PhD, runs the Pediatric UDP; May Malicdan, MD, PhD, manages the UDPs translational research program; and Camilo Toro, MD, is the master neurologist who directs the adult portion of the UDP. In the first 8 months of FY23, the UDP reviewed 183 applications and evaluated 59 patients accounting for 135 adjusted patient days in the Clinical Center. This pace continued during the last third of the year. In FY23, children comprised 40% of the patients; 26 diagnoses were made. These included a 14 year-old girl from Nigeria with rickets and fractures due to a de novo pathogenic variant in SLC4A1, a13 year-old boy with gliomatosis cerebri, a 6 year-old boy with poor development, hypotonia, and dysmorphisms due to EIF3F variants, a 42 year-old man with seizures, acidosis, and impaired hearing due to 77% heteroplasmy in muscle tRNA-His, a 54 year-old male with autosomal dominant progressive myopathy due to a splicing variant in MYH2, a 23 year-old male with spinocerebellar ataxia and delays due to biallelic variants in PRDX3, a 5 year-old girl and her sib with hypotonia, language delay, and stereotypic movements due to MEF2C mutations, a 64 year-old woman with adult polyglucosan body disease due to GBE1 mutations, a 14 year-old girl with rickets due to SLC4A1 mutations, a 28 year-old male with cerebral cavernous malformations due to a KRIT1 mutation, a 39 year-old woman with atypical mycobacterium and cranial nerve involvement, a 31 year-old male with unstable gait and peripheral neuropathy due to biallelic SETX mutations, a 47 year-old with moving toes syndrome, 27 and 18 year-old males with delays and parkinsonism due to WARS2 mutations, an 11 year-old girl with dysmorphisms, growth delay, intellectual disability, and liver failure due to biallelic variants in NBAS, 7 and 8 year-old girls with poor development, renal failure, and trifunctional protein deficiency due to HADHB mutations, a 56 year-old female with quadriceps-sparing myopathy due to GNE mutations, a 13 year-old girl from Albania with delays, stroke, apraxia, seizures, and brain dysmorphisms due to a CACNA1A mutation, a 38 year-old man with cerebellar ataxia due to a de novo RAB3A mutation, and a 3 year-old boy with encephalopathy and low selenium due to PSTK mutations. In the past year, the UDP was involved in the discovery of several new disease mechanisms, including an autoinflammatory disease, pansclerotic morphea, due to a gain-of-function STAT4 variant driving IL-6 inflammation and treatable with JAK-STAT inhibition. UDP bench researchers also described decreased ATG4D cysteine protease activity responsible for impaired autophagic degradation of damaged neuronal organelles in an 11 year-old boy with speech and motor impairment due to biallelic ATG4D mutations. A 20 year old female UDP patient manifested neuroregression and progressive spasticity with biallelic pathogenic SNAPC4 variants; UDP bench investigators determined that these mutations reduced the function of snRNA Activating Protein Complex 4, causing reduced snRNA gene transcription required for splicing function. UDP scientists and clinicians also contributed to the elucidation of decreased actin skeleton organization due to a de novo variant in the transcription factor gene, MRTFB, in an 18 year-old woman with developmental delays and apraxia. Finally, the UDP team expanded the phenotype of TUBB4B tubulopathy by describing renal Fanconi syndrome in a 2 year-old girl with a previously undescribed mutation in TUBB4B. The mutation affects the GTP binding site of TUB4B, impairs tubulin disassembly, and likely prevents movement of phosphate transporters to the apical surface of renal tubular cells for phosphate reabsorption. In FY 23, the UDP led or contributed to 23 publications, including one each in the New England Journal of Medicine, American Journal of Human Genetics, Brain, Science Advances, Human Molecular Genetics, and two in Genetics in Medicine. Dr. Toro described the molecular basis of ROSAH syndrome (gain-of-function ALPK1 variants), helped publish a broad characterization of African Nodding Syndrome, reported a de novo HK1 (hexokinase 1) variant as a cause of Boucher-Neuhauser syndrome, described a myopathy due to a splice variant in MYH2, contributed to an article on pituitary hypersecretion due to-loss of-function PAM variants, described the use of TNF blockers to prevent stroke in patients with Adenosine Deaminase 2 Deficiency, and summarized the genetic bases of UDP patients with intracerebral calcifications. Other Section members reported the mechanism of haploinsufficiency of KMT5B in impairing murine and human neurodevelopment, provided insights gleaned from the UDP, contributed to an elucidation of disorders of mitochondrial and nuclear genome stability related to TOP3A variants, and contributed to the elucidation of neuroimaging and skeletal features of KBG syndrome. UDP investigators collaborated on patient-related UDP projects with physicians and scientists from NCI, NICHD, NHLBI, NINDS, NIAID, NIDDK, NIMH, NIDCR, NEI, and NHGRI. Members of the UDP searched the UDP database, UDPICS, for variants in genes of interest for a dozen intramural investigators. The Program trained 8 postbacc IRTAs and two graduate students in FY23; 4 current trainees are first authors of published articles. Dr. Adams conducted a Bioinformatic Journal Club and delivered lectures at the Genome School and at other national and international forums. Dr. Gahl conducts weekly UDP patient rounds, attended by 70-80 aspiring physicians and scientists. For the international rare disease community, Gahl leads the Undiagnosed Diseases Network International (UDNI), a consortium of 161 physicians and scientists from 49 nations. In FY23, Gahl coordinated the 11th UDNI conference in Vienna, established a Champions Initiative to foster UDPs in developing nations, and published papers on the value of clinical networks for rare diseases and the unmet needs of undiagnosed patients in various countries. With colleagues, he wrote articles on the UDN, insights gleaned from the UDP, and the relationship between the UDNI and a new journal entitled Rare. Gahl also delivered 7 invited national and international talks that featured the UDP, including the Roscoe Brady Award lecture for WORLDSymposium.

23财年是NIH未经诊断的疾病计划根据学校税的资金运作的第一年，即基于其壁内研究预算的规模支持NIH临床中心的NIH研究所和中心。在过去的10年（2013 - 2022年）中，UDP由普通基金资助。医学博士William Gahl和医学博士的Adams博士，联合指导UDP；医学博士Cynthia tifft，经营小儿UDP； May Malicdan，医学博士，博士管理UDPS转化研究计划；医学博士卡米洛·托罗（Camilo Toro）是指导UDP成人部分的主要神经科医生。在23财年的前8个月中，UDP审查了183次申请，并评估了59名患者在临床中心进行了135个调整后的患者日。在最后三分之一的三分之一中，这种步伐持续了。在23财年，儿童占40％的患者；进行了26个诊断。其中包括一个来自尼日利亚的14岁女孩，由于SLC4A1中的从头致病性变异而引起的摇摇欲坠和骨折，A13岁的男孩患有胶质瘤病脑胶状体病脑，一个6岁的男孩，发育不良，低骨和畸形，由于EIF3F变体而导致的eif3f变体，酸性变体，酸性症状，酸度为7％，是酸性的，酸性的，是酸性的7％。 tRNA-His, a 54 year-old male with autosomal dominant progressive myopathy due to a splicing variant in MYH2, a 23 year-old male with spinocerebellar ataxia and delays due to biallelic variants in PRDX3, a 5 year-old girl and her sib with hypotonia, language delay, and stereotypic movements due to MEF2C mutations, a 64 year-old woman with adult polyglucosan body disease due to GBE1 mutations, a 14 year-old girl with rickets due to SLC4A1 mutations, a 28 year-old male with cerebral cavernous malformations due to a KRIT1 mutation, a 39 year-old woman with atypical mycobacterium and cranial nerve involvement, a 31 year-old male with unstable gait and peripheral neuropathy due to biallelic SETX突变是一个47岁的脚趾综合征，27岁和18岁的男性，由于Wars2突变而导致延迟和帕金森氏症，一个11岁的女孩，畸形，生长延迟，智力残疾，智力残疾和肝脏失败，由NBAS的BIALLELICS造成的Biallelic变异，具有较差的女性，由于发育率较差，肾脏失败的差异很差。 quadriceps-sparing myopathy due to GNE mutations, a 13 year-old girl from Albania with delays, stroke, apraxia, seizures, and brain dysmorphisms due to a CACNA1A mutation, a 38 year-old man with cerebellar ataxia due to a de novo RAB3A mutation, and a 3 year-old boy with encephalopathy and low selenium due to PSTK mutations. 在过去的一年中，UDP参与了几种新的疾病机制，包括自身炎症性疾病，Pansclototic Morphea，这是由于功能性的STAT4变体驱动IL-6炎症和JAK-STAT抑制作用。 UDP替补席研究人员还描述了降低的ATG4D半胱氨酸蛋白酶活性降低，导致一个11岁的男孩因双重ATG4D突变而导致的言语和运动障碍受损的神经元细胞器的自噬降解受损。一名20岁的女性UDP患者表现出具有双重致病SNAPC4变体的神经性和进行性痉挛。 UDP基准研究者确定这些突变降低了SnRNA激活蛋白质复合物4的功能，从而导致剪接功能所需的SnRNA基因转录减少。 UDP科学家和临床医生还为阐明肌动蛋白骨架组织减少而促进了转录因子基因MRTFB的从头变异，这是一名18岁患有发育迟缓和失用的女性。最后，UDP团队通过描述了一个2岁的女孩中的肾脏Fanconi综合征，扩大了TUBB4B肾小管病的表型。该突变会影响TUB4B的GTP结合位点，损害小管蛋白拆卸，并可能阻止磷酸转运蛋白向肾小管细胞的顶部运动进行磷酸盐的重吸收。在23财年中，UDP领导或贡献了23个出版物，其中包括新英格兰医学杂志，《美国人类遗传学》，《脑，科学进步》，人类分子遗传学以及两项医学遗传学的一份出版物。托罗博士描述了罗莎综合征（功能功能ALPK1变体）的分子基础，帮助发表了非洲点点头综合征的广泛表征，报道了从头开始的hk1（己糖酶1）变体是boucher-neuhauser综合征的一种原因，描述了由于跨性别的变化，造成了我的杂物，这些杂物是在我的杂物中造成的，造成了我在我的脑海中的变化，这些文章在我的脑海中造成了杂物，造成了我的杂物。功能性PAM变体描述了使用TNF阻滞剂防止腺苷脱氨酶2缺乏症患者中风，并总结了脑内钙化钙化的UDP患者的遗传碱基。 Other Section members reported the mechanism of haploinsufficiency of KMT5B in impairing murine and human neurodevelopment, provided insights gleaned from the UDP, contributed to an elucidation of disorders of mitochondrial and nuclear genome stability related to TOP3A variants, and contributed to the elucidation of neuroimaging and skeletal features of KBG syndrome. UDP研究人员与NCI，NICHD，NHLBI，NINDS，NIAID，NIDDK，NIMH，NIMH，NIMH，NIDCR，NEI和NHGRI的医生和科学家合作与患者相关的UDP项目合作。 UDP的成员搜索了UDP数据库UDPICS，为十几个壁内研究者寻找了感兴趣基因的变体。该计划在23财年培训了8个后BACC IRTA和两名研究生； 4名当前的学员是发表文章的第一作者。亚当斯博士举办了一个生物信息学期刊俱乐部，并在基因组学校以及其他国家和国际论坛上进行了讲座。 Gahl博士每周进行UDP患者巡回赛，由70-80名有抱负的医生和科学家参加。对于国际稀有疾病社区，Gahl领导了未诊断的疾病国际网络（UDNI），这是来自49个国家的161名医师和科学家的财团。在23财年，加尔协调了维也纳举行的第11届UDNI会议，建立了一项冠军倡议，以培养发展中国家的UDP，并发表了有关稀有疾病的临床网络价值以及各个国家未诊断患者的未满足需求的论文。与同事一起，他撰写了有关UDN的文章，从UDP收集的见解以及UDNI与新期刊之间的关系，名为Rare。 Gahl还发表了7次邀请的国家和国际演讲，其中包括UDP，包括Roscoe Brady奖的WorldSymposium。