The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach… or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments.

This paper focuses on the question of, "When is the best time to identify an individual at risk for a treatable genetic condition?" In this review, we describe a framework for considering the optimal timing for pursuing genetic and genomic screening for treatable genetic conditions incorporating a lifespan approach. Utilizing the concept of a carousel that represents the four broad time periods when critical decisions might be made around genetic diagnoses during a person's lifetime, we describe genetic testing during the prenatal period, the newborn period, childhood, and adulthood. For each of these periods, we describe the objectives of genetic testing, the current status of screening or testing, the near-term vision for the future of genomic testing, the advantages and disadvantages of each approach, and the feasibility and ethical considerations of testing and treating. The notion of a "Genomics Passbook" is one where an early genomic screening evaluation could be performed on each individual through a public health program, with that data ultimately serving as a "living document" that could be queried and/or reanalyzed at prescribed times during the lifetime of that person, or in response to concerns about symptoms of a genetic disorder in that individual.

American Journal of Medical Genetics Part C: Seminars in Medical GeneticsVolume 193, Issue 1 p. 5-6 INTRODUCTION Note from the editors Tiina K. Urv, Corresponding Author Tiina K. Urv [email protected] Division of Rare Diseases Research Innovation (DRDRI), National Center for Advancing Translational Science, National Institutes of Health, Bethesda, Maryland, USA Correspondence Tiina K. Urv, Division of Rare Diseases Research Innovation (DRDRI), National Center for Advancing Translational Science National Institutes of Health, Bethesda, MD, USA. Email: [email protected] Melissa A. Parisi, National Institute of Child Health and Human Development National Institutes of Health Bethesda, MD, USA. Email: [email protected]Search for more papers by this authorMelissa A. Parisi, Corresponding Author Melissa A. Parisi [email protected] National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA Correspondence Tiina K. Urv, Division of Rare Diseases Research Innovation (DRDRI), National Center for Advancing Translational Science National Institutes of Health, Bethesda, MD, USA. Email: [email protected] Melissa A. Parisi, National Institute of Child Health and Human Development National Institutes of Health Bethesda, MD, USA. Email: [email protected]Search for more papers by this author Tiina K. Urv, Corresponding Author Tiina K. Urv [email protected] Division of Rare Diseases Research Innovation (DRDRI), National Center for Advancing Translational Science, National Institutes of Health, Bethesda, Maryland, USA Correspondence Tiina K. Urv, Division of Rare Diseases Research Innovation (DRDRI), National Center for Advancing Translational Science National Institutes of Health, Bethesda, MD, USA. Email: [email protected] Melissa A. Parisi, National Institute of Child Health and Human Development National Institutes of Health Bethesda, MD, USA. Email: [email protected]Search for more papers by this authorMelissa A. Parisi, Corresponding Author Melissa A. Parisi [email protected] National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA Correspondence Tiina K. Urv, Division of Rare Diseases Research Innovation (DRDRI), National Center for Advancing Translational Science National Institutes of Health, Bethesda, MD, USA. Email: [email protected] Melissa A. Parisi, National Institute of Child Health and Human Development National Institutes of Health Bethesda, MD, USA. Email: [email protected]Search for more papers by this author First published: 23 March 2023 https://doi.org/10.1002/ajmg.c.32039Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES Brooks, P. J., Urv, T. K., & Parisi, M. A. (2023). Gene-targeted therapies: Overview and implications. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 193(1), 13–18. https://doi.org/10.1002/ajmg.c.32033 Garrison, L. P., Lo, A. W., Finkel, R. S., & Deverka, P. A. (2023). A review of economic issues for gene-targeted therapies: Value, affordability, and access. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 193(1), 64–76. https://doi.org/10.1002/ajmg.c.32037 Gaviglio, A. M., Skinner, M. W., Lou, L. J., Finkel, R. S., Augustine, E. F., & Goldenberg, A. J. (2023). Gene-targeted therapies: Towards equitable development, diagnosis, and access. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 193(1), 56–63. https://doi.org/10.1002/ajmg.c.32032 Lekstrom-Himes, J., Augustine, E. F., Brower, A., Defay, T., Finkel, R. S., McGuire, A. L., … Yu, T. W. (2023). Data sharing to advance gene-targeted therapies in rare diseases. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 193(1), 87–98. https://doi.org/10.1002/ajmg.c.32028 Lekstrom-Himes, J., Brooks, P. J., Koeberl, D. D., Brower, A., Goldenberg, A., Green, R. C., … Augustine, E. F. (2023). Moving away from one disease at a time: Screening, trial design, and regulatory implications of novel platform technologies. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 193(1), 30–43. https://doi.org/10.1002/ajmg.c.32031 National Institutes of Health. (2021). Gene-targeted therapies: Early diagnosis and equitable delivery. Retrieved from https://events-support.com/events/Gene-Targeted_Therapies_June_2021. Parisi, M. A., Caggana, M., Cohen, J. L., Gold, N. B., Morris, J. A., Orsini, J. J., … Wasserstein, M. P. (2023). When is the best time to screen and evaluate for treatable genetic disorders?: A lifespan perspective. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 193(1), 44–55. https://doi.org/10.1002/ajmg.c.32036 Vockley, J., Aartsma-Rus, A., Cohen, J. L., Cowsert, L. M., Howell, R. R., Yu, T. W., … Defay, T. (2022). Whole-genome sequencing holds the key to the success of gene-targeted therapies. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 193(1), 19–29. https://doi.org/10.1002/ajmg.c.32017 Vockley, J., Defay, T., Goldenberg, A. J., & Gaviglio, A. M. (2022). Scaling genetic resources: New paradigms for diagnosis and treatment of rare genetic disease. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 193(1), 77–86. https://doi.org/10.1002/ajmg.c.32016 Yu, T. W., Kingsmore, S. F., Green, R. C., MacKenzie, T., Wasserstein, M., Caggana, M., … Urv, T. K. (2023). Are we prepared to deliver gene-targeted therapies for rare diseases? American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 193(1), 7–12. https://doi.org/10.1002/ajmg.c.32029 Volume193, Issue1Special Issue: Gene‐Targeted Therapies: Early Diagnosis and Equitable DeliveryMarch 2023Pages 5-6 ReferencesRelatedInformation

Background: The current road to developing treatments for rare diseases is often slow, expensive, and riddled with risk. Change is needed to improve the process, both in how we think about rare disease treatment development and the infrastructure we build to support ongoing science. The National Institutes of Health (NIH)-supported Rare Diseases Clinical Research Network (RDCRN) was established to advance the diagnosis, management, and treatment of rare diseases and to promote highly collaborative, multi-site, patient-centric, translational, and clinical research. The current iteration of the RDCRN intends to build upon and enhance successful approaches within the network while identifying innovative methods to fill gaps and address needs in the approach to the rare disease treatment development process through innovation, collaboration, and clinical trial readiness. Objective: The objective of this paper is to provide an overview of the productivity and influence of the RDCRN since it was first established 20 years ago. Design and methods: Using a suite of tools available to NIH staff that provides access to a comprehensive, curated, extensively linked data set of global grants, patents, publications, clinical trials, and FDA-approved drugs, a series of queries were executed that conducted bibliometric, co-author, and co-occurrence analysis. Results: The results demonstrate that the entire RDCRN consortia and network has been highly productive since its inception. They have produced 2763 high-quality publications that have been cited more than 100,000 times, expanded international networks, and contributed scientifically to ten FDA-approved treatments for rare diseases. Conclusion: The RDCRN program has successfully addressed some significant challenges while developing treatments for rare diseases. However, looking to the future and being agile in facing new challenges that arise as science progresses is important.

Gene-targeted therapies (GTTs) are therapeutic platforms that are in principle applicable to large numbers of monogenic diseases. The rapid development and implementation of GTTs have profound implications for rare monogenic disease therapy development. This article provides a brief summary of the primary types of GTTs and a brief overview of the current state of the science. It also serves as a primer for the articles in this special issue.

Every year individuals experience symptoms that remain undiagnosed by healthcare providers. In the United States, these rare diseases are defined as a condition that affects fewer than 200,000 individuals. However, there are an estimated 7000 rare diseases, and there are an estimated 25-30 million Americans in total (7.6-9.2% of the population as of 2018) affected by such disorders. The NIH Common Fund Undiagnosed Diseases Network (UDN) seeks to provide diagnoses for individuals with undiagnosed disease. Mass spectrometry-based metabolomics and lipidomics analyses could advance the collective understanding of individual symptoms and advance diagnoses for individuals with heretofore undiagnosed disease. Here, we report the mass spectrometry-based metabolomics and lipidomics analyses of blood plasma, urine, and cerebrospinal fluid from 148 patients within the UDN and their families, as well as from a reference population of over 100 individuals with no known metabolic diseases. The raw and processed data are available to the research community so that they might be useful in the diagnoses of current or future patients suffering from undiagnosed disorders.

It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to implement these desired changes into postgraduate medical training and engage learners is still unclear. We developed a novel elective rotation in ‘Genomic Medicine and Undiagnosed Diseases’ for categorical Internal Medicine Residents to address this educational gap and serve as an adaptable model for training that can be applied broadly across different specialties and at other institutions. Key curriculum goals achieved include increased understanding about genetic testing modalities and tools available for diagnosis and risk analysis, the role of genetics-trained allied health professionals, and indications and limitations of genetic and genomic testing in both rare and common conditions.

Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next-generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22 kb homozygous deletion in SLC12A2, which encodes for sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein abundance when compared with control. Loss of Slc12a2 in mice has been shown to lead to deafness, abnormal neuronal growth and migration, severe gastrointestinal abnormalities, and absent salivation. Together with the described phenotype of the Slc12a2-knockout mouse model, our results suggest that the absence of functional SLC12A2 causes a new genetic syndrome and is crucial for the development of auditory, neurologic, and gastrointestinal tissues.

BackgroundRare variants (RV) in immunoglobulin mu-binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot-Marie-Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associated with CMT, with different possible inheritance patterns. Methods and ResultsAn 11-year-old female with motor delays was found to have distal atrophy, weakness, and areflexia without bulbar or sensory findings. Her clinical evaluation was unrevealing. Whole exome sequencing (WES) revealed a maternally inherited IGHMBP2 RV (c.1730T>C) predicted to be pathogenic, but no variant on the other allele was identified. Deletion and duplication analysis was negative. She was referred to the Undiagnosed Disease Network (UDN) for further evaluation. Whole genome sequencing (WGS) confirmed the previously identified IGHMBP2 RV and identified a paternally inherited non-coding IGHMBP2 RV. This was predicted to activate a cryptic splice site perturbing IGHMBP2 splicing. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis was consistent with activation of the cryptic splice site. The abnormal transcript was shown to undergo nonsense-mediated decay (NMD), resulting in halpoinsufficiency. ConclusionThis case demonstrates the deficiencies of WES and traditional molecular analyses and highlights the advantages of utilization of WGS and functional studies.

BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative. METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology. RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory. CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.

There are approximately 7,000 rare diseases affecting 25-30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%-41% of the patients receive a molecular diagnosis. The remaining three-fifths to three-quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non-diagnostic ES results, but strategic follow-up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow-up of cases where ES is non-diagnostic. Solved case examples illustrate different types of non-diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype-disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.

Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.

Objective To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. Methods We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. Results The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. <

AbstractBackgroundFamily screening of a 48‐year‐old male with recently diagnosed IgG4‐related disease (IgG4‐RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.MethodsWe performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4‐RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.ResultsThe three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T‐lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical‐turn‐helix structure, unable to adopt a stable conformation. The proband and the two sons had 5–10‐fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4‐RD cohort, showing enrichment in idiopathic IgG4‐RD.ConclusionsThe presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4‐RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4‐RD supports the likelihood of participation in disease.