Each month, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Catch up on the latest RDCRN research below.
Jump to:
- Developmental Synaptopathies Consortium (DSC)
- Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC)
- Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
- North American Mitochondrial Disease Consortium (NAMDC)
Listen to these summaries on the Rare Research Report podcast.
Developmental Synaptopathies Consortium (DSC)
Assessing the Current State of Professional Society Guidelines for Genetic Testing of Neurodevelopmental Disorders
Neurodevelopmental disorders are a spectrum of conditions that affect how the brain functions. These disorders can impact many different areas of childhood development, including motor, problem solving, social-communication, and adaptive skills. Genetic testing of patients with neurodevelopmental disorders is critical for diagnosis, medical management, and access to precision therapies. However, the creation and implementation of professional society practice guidelines for genetic testing can be challenging due to the rapid evolution of approaches.
In this review, authors assessed the current state of United States professional societies' guidelines for genetic testing of neurodevelopmental disorders. The team focused on disorders including unexplained global developmental delay, intellectual disability, autism spectrum disorder, and cerebral palsy. Authors describe several shortcomings of current guidelines and express the need for a unified, frequently updated, and easily accessible cross-specialty society guideline.
Srivastava S, Cole JJ, Cohen JS, Chopra M, Smith HS, Deardorff MA, Pedapati E, Corner B, Anixt JS, Jeste S, Sahin M, Gurnett CA, Campbell CA; Intellectual and Developmental Disabilities Research Center (IDDRC) Workgroup on Advocating for Access to Genomic Testing. Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders. Ann Neurol. 2024 Sep 25. doi: 10.1002/ana.27045. Epub ahead of print. PMID: 39319594.
Evaluating the Prevalence and Risk of Aortic Root Dilation in Patients with Phelan-McDermid Syndrome
Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder that results from the loss of a small piece of chromosome 22. While many features of PMS are well-understood, less is known about cardiovascular abnormalities.
In this study, researchers evaluated the prevalence and risk of aortic root dilation (ARD) in patients with PMS. Among 59 individuals with PMS, the team analyzed echocardiographic and genetic reports for aortic root measurements and genetic variant data.
Results reveal that eight participants had ARD, which was associated with larger chromosome 22 deletions. Participants with ARD also had significantly more genes deleted on chromosome 22 than participants without ARD. Authors note that these results could help identify individuals with PMS who are at higher risk for ARD.
Gluckman J, Levy T, Friedman K, Garces F, Filip-Dhima R, Quinlan A, Iannotti I, Pekar M, Hernandez AL, Nava MT, Kravets E, Siegel A, Bernstein JA, Berry-Kravis E, Powell CM, Soorya LV, Thurm A, Srivastava S, Buxbaum JD, Sahin M, Kolevzon A, Gelb BD; Developmental Synaptopathies Consortium. Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome. Am J Med Genet A. 2024 Sep 11:e63872. doi: 10.1002/ajmg.a.63872. Epub ahead of print. PMID: 39257296.
Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC)
Evaluating the O-GlcNAc Transferase Interactome to Identify Potential Mechanistic Targets for OGT-Congenital Disorder of Glycosylation
O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG) is an inherited disorder caused by dysfunction of the OGT enzyme that affects a complex process in the body called glycosylation. Pathogenic variants associated with OGT-CDG are thought to disrupt the OGT interactome, which consists of interactions between thousands of proteins.
In this review paper, researchers evaluated the OGT interactome to identify potential mechanistic targets for OGT-CDG studies. The team also discussed clinical features of OGT-CDG and the biochemical effects of mutations.
Authors note that as more OGT variants are characterized and additional patients are identified, it may become possible to identify a set of common alterations in OGT function as well as a core set of clinical features of OGT-CDG, which could help improve diagnosis.
Mayfield JM, Hitefield NL, Czajewski I, Vanhye L, Holden L, Morava E, van Aalten DMF, Wells L. O-GlcNAc transferase congenital disorder of glycosylation (OGT-CDG): Potential mechanistic targets revealed by evaluating the OGT interactome. J Biol Chem. 2024 Sep;300(9):107599. doi: 10.1016/j.jbc.2024.107599. Epub 2024 Jul 24. PMID: 39059494; PMCID: PMC11381892.
Genetic Disorders of Mucociliary Clearance Consortium (GDMCC)
Identifying a Pathogenic Non-Coding Variant in a Genetically Unsolved Case of Primary Ciliary Dyskinesia
Primary ciliary dyskinesia (PCD) is a genetic condition in which mucociliary clearance of the lungs is impaired, leading to accumulation of harmful particles and pathogens trapped within mucus. Variation in the non-coding genome can sometimes cause genetic diseases like PCD. However, it can be challenging to predict whether these variants will lead to disease.
In this study, researchers identified a pathogenic non-coding variant in a genetically unsolved case of PCD. The team used complementary RNA sequencing and targeted long-read DNA sequencing approaches to uncover a non-coding deletion in the 5’ untranslated region of the SPAG1 gene in a patient with PCD.
Results highlight the importance of investigating the non-coding genome in patients with “missing” disease-causing variants. Authors note that both RNA and long-read DNA sequencing can be used to identify pathogenic non-coding variants in patients with unexplained genetic diseases.
Beaman MM, Yin W, Smith AJ, Sears PR, Leigh MW, Ferkol TW, Kearney B, Olivier KN, Kimple AJ, Clarke S, Huggins E, Nading E, Jung SH, Iyengar AK, Zou X, Dang H, Barrera A, Majoros WH, Rehder CW, Reddy TE, Ostrowski LE, Allen AS, Knowles MR, Zariwala MA, Crawford GE. Promoter Deletion Leading to Allele Specific Expression in a Genetically Unsolved Case of Primary Ciliary Dyskinesia. Am J Med Genet A. 2024 Oct 4:e63880. doi: 10.1002/ajmg.a.63880. Epub ahead of print. PMID: 39364610.
North American Mitochondrial Disease Consortium (NAMDC)
Identifying a New and Potentially Treatable Cause of Mitochondrial DNA Depletion/Deletions Syndrome
Mitochondrial DNA depletion/deletions syndrome (MDDS) is a group of disorders in which copies of the DNA within mitochondria (specialized cell structures that produce energy) are severely reduced in number. MDDS results in impaired energy production required for proper functioning of the body tissues and organs, affecting the brain, liver, digestive system, nerves, and skeletal muscles.
In this study, researchers identified a new and potentially treatable cause of MDDS. The team performed whole exome sequencing to investigate pathogenic variants in four patients who presented with MDDS symptoms, but did not have a known genetic cause.
Results revealed pathogenic variants in the GUK1 gene in all four patients and that the GUK1 protein has a long mitochondrial isoform and a short cytosolic isoform. The team also identified effective in vitro therapeutic strategies to restore mitochondrial DNA levels, highlighting potential treatments for this disorder. Authors note that GUK1 deficiency is the first example of impaired nucleotide monophosphate kinase causing MDDS.
Hidalgo-Gutierrez A, Shintaku J, Ramon J, Barriocanal-Casado E, Pesini A, Saneto RP, Garrabou G, Milisenda JC, Matas-Garcia A, Gort L, Ugarteburu O, Gu Y, Koganti L, Wang T, Tadesse S, Meneri M, Sciacco M, Wang S, Tanji K, Horwitz MS, Dorschner MO, Mansukhani M, Comi GP, Ronchi D, Marti R, Ribes A, Tort F, Hirano M. Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease. Ann Neurol. 2024 Sep 4. doi: 10.1002/ana.27071. Epub ahead of print. PMID: 39230499.
Using a Proteomics-Based Approach for Ultra-Rapid Diagnosis of Pyruvate Dehydrogenase Complex Deficiency
Pyruvate dehydrogenase complex (PDH) deficiency is a mitochondrial disease that limits the breakdown of carbohydrates for energy production, leading to high levels of lactic acid, which can be life-threatening. Diagnosing mitochondrial diseases like PDH is often complex, with limited options for additional tests after a negative rapid whole-genome sequencing result.
In this study, researchers used a proteomics-based approach for ultra-rapid diagnosis of PDH deficiency. The study included a neonatal patient presenting with severe lactic acidosis on the second day of life and a negative initial ultra-rapid genome sequencing report. With multi-omics techniques, the team identified PDHX from absence of peptides in the cells, leading to the discovery of a pathogenic variant in the PDHX gene. Subsequent testing in the following months confirmed a diagnosis of PDH deficiency, and the patient was successfully treated for lactic acidosis with dichloroacetate.
Results highlight the power of rapid proteomics in guiding genomic analysis. Authors also note that these results identify dichloroacetate as a promising potential therapy for lactic acidosis in PDH deficiency.
Starosta RT, Larson AA, Meeks NJL, Gracie S, Friederich MW, Gaughan SM, Baker PR 2nd, Knupp KG, Michel CR, Reisdorph R, Hock DH, Stroud DA, Wood T, Van Hove JLK. An integrated multi-omics approach allowed ultra-rapid diagnosis of a deep intronic pathogenic variant in PDHX and precision treatment in a neonate critically ill with lactic acidosis. Mitochondrion. 2024 Oct 15;79:101973. doi: 10.1016/j.mito.2024.101973. Epub ahead of print. PMID: 39413893.
The Rare Diseases Clinical Research Network (RDCRN) is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). Now in its fourth five-year funding cycle, RDCRN is a partnership with funding and programmatic support provided by Institutes, Centers, and Offices across NIH, including the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, the National Institute of Mental Health, and the Office of Dietary Supplements.
