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The utilization of genetics in medical care has enhanced the utility of precision medicine and hence increased the need for clinical genetic services. These services have reduced the costs and expanded the availability of genetic testing, but their use is limited in certain populations. This study explores the access to clinical genetic services for Michigan patients referred to a genetics clinic on the western side of the state. Factors included the travel distance (miles), wait time for appointment (days from the referral date to the date of first appointment), population demographics, and cultural characteristics. A retrospective record review of all aged patients (n = 568) referred to a genetics clinic in 2018 demonstrated that all patients were insured (100%), of which majority were white-non-Hispanic (90.7%), more than half were < 10 years of age at referral (53.3%), and most of them kept their first appointment (93.5%). Our analysis showed that the wait time was associated with referral non-compliance, p < 0.01. Adjusting for all variables, for each additional day in wait time, patients had 1% increased risk of not seeking clinical genetic services (OR = 1.01, 90% CI [1.01, 1.02]). Policies to encourage genetic service utilization and improve equitable access to precision health are needed. An opportunity exists for strategies that broaden and add diverse populations to those receiving genetic services.
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The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now. Here we show that CAMK2D plays an important role in neurodevelopment not only in mice but also in humans. We identified eight individuals harboring heterozygous variants in CAMK2D who display symptoms of intellectual disability, delayed speech, behavioral problems, and dilated cardiomyopathy. The majority of the variants tested lead to a gain of function (GoF), which appears to cause both neurological problems and dilated cardiomyopathy. In contrast, loss-of-function (LoF) variants appear to induce only neurological symptoms. Together, we describe a cohort of individuals with neurodevelopmental disorders and cardiac anomalies, harboring pathogenic variants in CAMK2D, confirming an important role for the CAMK2D isozyme in both heart and brain function.
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Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Cardiomiopatía Dilatada , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Animales , Humanos , Ratones , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Corazón , Trastornos del Neurodesarrollo/genéticaRESUMEN
Gene therapy holds promise as a life-changing option for individuals with genetic variants that give rise to disease. FDA-approved gene therapies for Spinal Muscular Atrophy (SMA), cerebral adrenoleukodystrophy, ß-Thalassemia, hemophilia A/B, retinal dystrophy, and Duchenne Muscular Dystrophy have generated buzz around the ability to change the course of genetic syndromes. However, this excitement risks over-expansion into areas of genetic disease that may not fit the current state of gene therapy. While in situ (targeted to an area) and ex vivo (removal of cells, delivery, and administration of cells) approaches show promise, they have a limited target ability. Broader in vivo gene therapy trials have shown various continued challenges, including immune response, use of immune suppressants correlating to secondary infections, unknown outcomes of overexpression, and challenges in driving tissue-specific corrections. Viral delivery systems can be associated with adverse outcomes such as hepatotoxicity and lethality if uncontrolled. In some cases, these risks are far outweighed by the potentially lethal syndromes for which these systems are being developed. Therefore, it is critical to evaluate the field of genetic diseases to perform cost-benefit analyses for gene therapy. In this work, we present the current state while setting forth tools and resources to guide informed directions to avoid foreseeable issues in gene therapy that could prevent the field from continued success.
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Bachmann-Bupp syndrome (BABS) is a neurodevelopmental disorder characterized by developmental delay, hypotonia, and varying forms of non-congenital alopecia. The condition is caused by 3'-end mutations of the ornithine decarboxylase 1 (ODC1) gene, which produce carboxy (C)-terminally truncated variants of ODC, a pyridoxal 5'-phosphate-dependent enzyme. C-terminal truncation of ODC prevents its ubiquitin-independent proteasomal degradation and leads to cellular accumulation of ODC enzyme that remains catalytically active. ODC is the first rate-limiting enzyme that converts ornithine to putrescine in the polyamine pathway. Polyamines (putrescine, spermidine, spermine) are aliphatic molecules found in all forms of life and are important during embryogenesis, organogenesis, and tumorigenesis. BABS is an ultra-rare condition with few reported cases, but it serves as a convincing example for drug repurposing therapy. α-Difluoromethylornithine (DFMO, also known as eflornithine) is an ODC inhibitor with a strong safety profile in pediatric use for neuroblastoma and other cancers as well as West African sleeping sickness (trypanosomiasis). Patients with BABS have been treated with DFMO and have shown improvement in hair growth, muscle tone, and development.
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Putrescina , Espermidina , Humanos , Niño , Putrescina/metabolismo , Putrescina/farmacología , Espermidina/metabolismo , Espermidina/farmacología , Poliaminas/metabolismo , Poliaminas/farmacología , Espermina/metabolismo , Espermina/farmacología , Eflornitina/farmacologíaRESUMEN
Recent identification of four additional polyaminopathies, including Bachmann-Bupp syndrome, have benefited from previous research on Snyder-Robinson syndrome in order to advance from research to treatment more quickly. As a result of the discovery of these conditions, the potential for treatment within this pathway, and for other possible unidentified polyaminopathies, the International Center for Polyamine Disorders (ICPD) was created to help promote understanding of these conditions, research opportunities, and appropriate care for families. This case study provides insights from two new patients diagnosed with Bachmann-Bupp syndrome, further expanding our understanding of this ultra-rare condition, as well as a general discussion about other known polyaminopathies. This work also presents considerations for collaborative research efforts across these conditions, along with others that are likely to be identified in time, and outlines the role that the ICPD hopes to fill as more patients with these polyaminopathies continue to be identified and diagnosed.
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Eflornitina , Poliaminas , Humanos , Poliaminas/metabolismoRESUMEN
Insulin is amongst the human genome's most well-studied genes/proteins due to its connection to metabolic health. Within this article, we review literature and data to build a knowledge base of Insulin (INS) genetics that influence transcription, transcript processing, translation, hormone maturation, secretion, receptor binding, and metabolism while highlighting the future needs of insulin research. The INS gene region has 2076 unique variants from population genetics. Several variants are found near the transcriptional start site, enhancers, and following the INS transcripts that might influence the readthrough fusion transcript INS-IGF2. This INS-IGF2 transcript splice site was confirmed within hundreds of pancreatic RNAseq samples, lacks drift based on human genome sequencing, and has possible elevated expression due to viral regulation within the liver. Moreover, a rare, poorly characterized African population-enriched variant of INS-IGF2 results in a loss of the stop codon. INS transcript UTR variants rs689 and rs3842753, associated with type 1 diabetes, are found in many pancreatic RNAseq datasets with an elevation of the 3'UTR alternatively spliced INS transcript. Finally, by combining literature, evolutionary profiling, and structural biology, we map rare missense variants that influence preproinsulin translation, proinsulin processing, dimer/hexamer secretory storage, receptor activation, and C-peptide detection for quasi-insulin blood measurements.
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Diabetes Mellitus Tipo 1 , Medicina de Precisión , Humanos , Proinsulina , Diabetes Mellitus Tipo 1/genética , Páncreas , GenómicaRESUMEN
The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan's Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project's impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95-214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.
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The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype-phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 gnomAD, 485 ClinVar, 1174 Geno2MP, and 4313 COSMIC human variants. We identified, within the HMG (High Mobility Group)- box, twenty-seven amino acids with changes in multiple SOX proteins annotated to clinical pathologies. These sites were screened through Geno2MP medical phenotypes, revealing novel SOX15 R104G associated with musculature abnormality and SOX8 R159G with intellectual disability. Within gnomAD, SOX18 E137K (rs201931544), found within the HMG box of ~0.8% of Latinx individuals, is associated with seizures and neurological complications, potentially through blood-brain barrier alterations. A total of 56 highly conserved variants were found at sites outside the HMG-box, including several within the SOX2 HMG-box-flanking region with neurological associations, several in the SOX9 dimerization region associated with Campomelic Dysplasia, SOX14 K88R (rs199932938) flanking the HMG box associated with cardiovascular complications within European populations, and SOX7 A379V (rs143587868) within an SOXF conserved far C-terminal domain heterozygous in 0.716% of African individuals with associated eye phenotypes. This SOX data compilation builds a robust genotype-to-phenotype association for a gene family through more robust ortholog data integration.
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Proteínas del Grupo de Alta Movilidad , Factores de Transcripción SOX , Humanos , Proteínas del Grupo de Alta Movilidad/química , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Factores de Transcripción SOX/genética , Secuencia de Aminoácidos , Dimerización , Genotipo , Factores de Transcripción SOXF/genética , Factores de Transcripción SOXF/metabolismo , Factores de Transcripción SOXB2/genética , Factores de Transcripción SOXB2/metabolismo , Factores de Transcripción SOXE/genéticaRESUMEN
BACKGROUND: Noonan Syndrome is caused by variants in a variety of genes found in the RAS/MAPK pathway. As more causative genes for Noonan Syndrome have been identified, more phenotype variability has been found, particularly congenital heart defects. Here, we report a case of dilated coronary arteries in a pediatric patient with a RIT1 variant to add to the body of literature around this rare presentation of Noonan Syndrome. CASE PRESENTATION: A 2-month-old female was admitted due to increasing coronary artery dilation and elevated inflammatory markers. Rapid whole genome sequencing was performed and a likely pathogenic RIT1 variant was detected. This gene has been associated with a rare form of Noonan Syndrome and associated heart defects. Diagnosis of the RIT1 variant also gave reassurance about the patient's cardiac findings and allowed for more timely discharge as she was discharged to home the following day. CONCLUSIONS: This case highlights the importance of the association between dilated coronary arteries and Noonan syndrome and that careful cardiac screening should be advised in patients diagnosed with Noonan syndrome. In addition, this case emphasizes the importance of involvement of other subspecialities to determine a diagnosis. Through multidisciplinary medicine, the patient was able to return home in a timely manner with a diagnosis and the reassurance that despite her dilated coronary arteries and elevated inflammatory markers there was no immediate concern to her health.
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Cardiopatías Congénitas , Síndrome de Noonan , Humanos , Femenino , Síndrome de Noonan/complicaciones , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Vasos Coronarios/patología , Proteínas ras/metabolismo , Fenotipo , MutaciónRESUMEN
Bachmann-Bupp syndrome (OMIM #619075) is a novel autosomal dominant disorder caused by variants in the c-terminus of the ornithine decarboxylase 1 gene, resulting in increased levels of ornithine decarboxylase. This case report includes two patients diagnosed with Bachmann-Bupp syndrome who were treated with difluoromethylornithine through compassionate use approval from the United States Food and Drug Administration. In both patients, treatment with difluoromethylornithine has resulted in improved dermatologic signs, including regrowth of eyebrow and scalp hair and cessation of recurrent follicular cyst development.
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Eflornitina , Ornitina Descarboxilasa , Estados Unidos , Humanos , Eflornitina/uso terapéutico , Ornitina Descarboxilasa/genética , Inhibidores de la Ornitina Descarboxilasa , OrnitinaRESUMEN
The small GTPase family is well-studied in cancer and cellular physiology. With 162 annotated human genes, the family has a broad expression throughout cells of the body. Members of the family have multiple exons that require splicing. Yet, the role of splicing within the family has been underexplored. We have studied the splicing dynamics of small GTPases throughout 41,671 samples by integrating Nanopore and Illumina sequencing techniques. Within this work, we have made several discoveries. 1). Using the GTEx long read data of 92 samples, each small GTPase gene averages two transcripts, with 83 genes (51%) expressing two or more isoforms. 2). Cross-tissue analysis of GTEx from 17,382 samples shows 41 genes (25%) expressing two or more protein-coding isoforms. These include protein-changing transcripts in genes such as RHOA, RAB37, RAB40C, RAB4B, RAB5C, RHOC, RAB1A, RAN, RHEB, RAC1, and KRAS. 3). The isolation and library technique of the RNAseq influences the abundance of non-sense-mediated decay and retained intron transcripts of small GTPases, which are observed more often in genes than appreciated. 4). Analysis of 16,243 samples of "Blood PAXgene" identified seven genes (3.7%; RHOA, RAB40C, RAB4B, RAB37, RAB5B, RAB5C, RHOC) with two or more transcripts expressed as the major isoform (75% of the total gene), suggesting a role of genetics in altering splicing. 5). Rare (ARL6, RAB23, ARL13B, HRAS, NRAS) and common variants (GEM, RHOC, MRAS, RAB5B, RERG, ARL16) can influence splicing and have an impact on phenotypes and diseases. 6). Multiple genes (RAB9A, RAP2C, ARL4A, RAB3A, RAB26, RAB3C, RASL10A, RAB40B, and HRAS) have sex differences in transcript expression. 7). Several exons are included or excluded for small GTPase genes (RASEF, KRAS, RAC1, RHEB, ARL4A, RHOA, RAB30, RHOBTB1, ARL16, RAP1A) in one or more forms of cancer. 8). Ten transcripts are altered in hypoxia (SAR1B, IFT27, ARL14, RAB11A, RAB10, RAB38, RAN, RIT1, RAB9A) with RHOA identified to have a transient 3'UTR RNA base editing at a conserved site found in all of its transcripts. Overall, we show a remarkable and dynamic role of splicing within the small GTPase family that requires future explorations.
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We provide the first study of two siblings with a novel autosomal recessive LRP1-related syndrome identified by rapid genome sequencing and overlapping multiple genetic models. The patients presented with respiratory distress, congenital heart defects, hypotonia, dysmorphology, and unique findings, including corneal clouding and ascites. Both siblings had compound heterozygous damaging variants, c.11420G > C (p.Cys3807Ser) and c.12407T > G (p.Val4136Gly) in LRP1, in which segregation analysis helped dismiss additional variants of interest. LRP1 analysis using multiple human/mouse data sets reveals a correlation to patient phenotypes of Peters plus syndrome with additional severe cardiomyopathy and blood vessel development complications linked to neural crest cells.
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Labio Leporino , Conducto Arterioso Permeable , Cardiopatías Congénitas , Deformidades Congénitas de las Extremidades , Animales , Humanos , Ratones , Labio Leporino/complicaciones , Enfermedades de la Córnea/metabolismo , Conducto Arterioso Permeable/complicaciones , Conducto Arterioso Permeable/genética , Deformidades Congénitas de las Extremidades/complicaciones , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Síndrome , Enfermedades Óseas/complicaciones , Enfermedades Óseas/genética , Enfermedades Óseas/metabolismo , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/metabolismoRESUMEN
Exciting new developments in biomedical and computational sciences provide an extraordinary and unparalleled opportunity to compile, connect, and analyze multiple types of "big data," driving the development of personalized medicine. These insights must begin in early life (ie, pregnancy, neonatal, and infancy) and focus on early prevention, diagnosis, and intervention-areas of medicine where pediatricians are poised to lead the way to a personalized medicine future. The rapid growth of genomics (including pharmacogenomics), transcriptomics, and related "omics" has revolutionized the diagnosis of rare monogenic disorders. It is now clarifying the pathogenesis of complex conditions ranging from autism spectrum disorder to asthma. Collaborations between clinicians and basic scientists integrating multiomics approaches in evaluating children with severe illness are transforming the fields of perinatal, neonatal, and pediatric critical care medicine. Improvements in rapid diagnostic and prognostic information suggest that pediatric personalized medicine is under way and has an exciting future. [Pediatr Ann. 2022;51(10):e381-e386.].
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Trastorno del Espectro Autista , Pediatría , Niño , Femenino , Genómica , Humanos , Recién Nacido , Farmacogenética , Medicina de Precisión , EmbarazoRESUMEN
We report a case of a 38-year-old female with an FLNA variant who underwent valve-sparing aortic root replacement. FLNA encodes Filamin A, an actin-binding protein. Our patient had aortic root dilation due to this variant. Aortic root repair was conducted using the David procedure, with modifications to account for tissue fragility associated with this genetic condition. This case demonstrates the value of patient-specific genetic information for the timing of surgery and operative course planning.
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Insuficiencia de la Válvula Aórtica , Válvula Aórtica , Femenino , Humanos , Adulto , Válvula Aórtica/cirugía , Filaminas/genética , Resultado del Tratamiento , Reimplantación , Aorta/cirugía , Insuficiencia de la Válvula Aórtica/cirugía , Estudios RetrospectivosRESUMEN
Genomics has grown exponentially over the last decade. Common variants are associated with physiological changes through statistical strategies such as Genome-Wide Association Studies (GWAS) and quantitative trail loci (QTL). Rare variants are associated with diseases through extensive filtering tools, including population genomics and trio-based sequencing (parents and probands). However, the genomic associations require follow-up analyses to narrow causal variants, identify genes that are influenced, and to determine the physiological changes. Large quantities of data exist that can be used to connect variants to gene changes, cell types, protein pathways, clinical phenotypes, and animal models that establish physiological genomics. This data combined with bioinformatics including evolutionary analysis, structural insights, and gene regulation can yield testable hypotheses for mechanisms of genomic variants. Molecular biology, biochemistry, cell culture, CRISPR editing, and animal models can test the hypotheses to give molecular variant mechanisms. Variant characterizations can be a significant component of educating future professionals at the undergraduate, graduate, or medical training programs through teaching the basic concepts and terminology of genetics while learning independent research hypothesis design. This article goes through the computational and experimental analysis strategies of variant characterization and provides examples of these tools applied in publications. © 2022 American Physiological Society. Compr Physiol 12:3303-3336, 2022.
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Estudio de Asociación del Genoma Completo , Genómica , Animales , Biología Computacional , Predisposición Genética a la Enfermedad , Humanos , FenotipoRESUMEN
We aimed to characterize knowledge and attitudes about rapid whole genome sequencing (rWGS) implementation of a broad constituency of healthcare professionals at hospitals participating in a statewide initiative to implement rWGS for hospitalized neonates and children up to 18 years of age meeting clinical criteria for testing. We surveyed 307 healthcare professionals from eight hospitals about their knowledge and attitudes regarding rWGS. We examined survey internal reliability using exploratory factor analysis and associations between respondent characteristics and attitudes toward rWGS with linear regression. We thematically analyzed free-text responses. Views about rWGS implementation in respondents' own setting and respondents' personal capability to implement rWGS were generally neutral (M = 3.44 (SD = 0.74); M = 3.30 (SD = 0.85), respectively). Views about the potential for rWGS in clinical practice were overall positive (M = 4.12 (SD = 0.57)). The degree of positivity of attitudes about rWGS was strongly influenced by perceived knowledge, clinical or non-clinical role, concerns about future insurance coverage for rWGS as a first-tier test, and future adverse impact of genomics health information on patients or families. We identified several actionable factors influencing attitudes toward rWGS of pediatric healthcare professionals. Expanded education and ongoing implementation research are needed for the full potential of rWGS in pediatrics to be realized.
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Predicting genotype-to-phenotype correlations from genomic variants has been challenging, particularly for genes that have a complex balance of dominant and recessive inheritance for phenotypes. Variants in NMDA receptor components GRIN1, GRIN2A, and GRIN2B cause a myriad of dominant disease phenotypes, with the most common being epilepsy and autism spectrum disorder. Starting from the analysis of a variant of uncertain significance (VUS, GRIN2A G760S), we realized the need for tools to map dominant variants for the components of the NMDA receptor. Some variants within GRIN1, GRIN2A, and GRIN2B exert dominant epilepsy and developmental delay, yet other amino acid variants are conserved and predicted to alter protein function but do not have dominant phenotypes. Common variant annotation tools are not powered to determine pathogenic dominant outcomes. To address this gap, we integrated sequence and structural analyses for GRIN1, GRIN2A, and GRIN2B. Using this approach, we determined that paralog homology mapping and topology can segregate dominant variants, with an elevation of intermolecular contacts between the subunits. Furthermore, demonstrating the general utility of our methodology, we show that 25 VUS within ClinVar also reach a dominant variant annotation, including the GRIN2A G760S variant. Our work suggests paralog homology and protein topology as a powerful strategy within the receptor complex to resolve dominant genetic variants relative to variants that would fit a recessive inheritance, requiring two damaging variants. These strategies should be tested in additional dominant genetic disorders to determine the broader utility.
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Trastorno del Espectro Autista , Epilepsia , Epilepsia/genética , Humanos , N-Metilaspartato/genética , Fenotipo , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
In the age of genomics, public understanding of complex scientific knowledge is critical. To combat reductionistic views, it is necessary to generate and organize educational material and data that keep pace with advances in genomics. The view that CCR5 is solely the receptor for HIV gave rise to demand to remove the gene in patients to create host HIV resistance, underestimating the broader roles and complex genetic inheritance of CCR5. A program aimed at providing research projects to undergraduates, known as CODE, has been expanded to build educational material for genes such as CCR5 in a rapid approach, exposing students and trainees to large bioinformatics databases and previous experiments for broader data to challenge commitment to biological reductionism. Our students organize expression databases, query environmental responses, assess genetic factors, generate protein models/dynamics, and profile evolutionary insights into a protein such as CCR5. The knowledgebase generated in the initiative opens the door for public educational information and tools (molecular videos, 3D printed models, and handouts), classroom materials, and strategy for future genetic ideas that can be distributed in formal, semiformal, and informal educational environments. This work highlights that many factors are missing from the reductionist view of CCR5, including the role of missense variants or expression of CCR5 with neurological phenotypes and the role of CCR5 and the delta32 variant in complex critical care patients with sepsis. When connected to genomic stories in the news, these tools offer critically needed Ethical, Legal, and Social Implication (ELSI) education to combat biological reductionism.
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Genómica/ética , Infecciones por VIH/prevención & control , VIH-1/patogenicidad , Receptores CCR5/genética , Internalización del Virus , Bases de Datos Genéticas , Resistencia a la Enfermedad/genética , Evolución Molecular , Predisposición Genética a la Enfermedad , Genómica/educación , Genómica/legislación & jurisprudencia , Genómica/métodos , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/metabolismo , Humanos , Difusión de la Información/ética , Difusión de la Información/legislación & jurisprudencia , Mutación Missense , Receptores CCR5/metabolismoRESUMEN
Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.
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Alopecia/genética , Discapacidades del Desarrollo/genética , Transportadores de Ácidos Dicarboxílicos/genética , Megalencefalia/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Adolescente , Adulto , Alopecia/diagnóstico , Alopecia/tratamiento farmacológico , Alopecia/patología , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/tratamiento farmacológico , Eflornitina/uso terapéutico , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Masculino , Megalencefalia/diagnóstico por imagen , Megalencefalia/tratamiento farmacológico , Megalencefalia/patología , Neuroimagen , Fenotipo , Poliaminas/metabolismo , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Convulsiones/genética , Convulsiones/patología , Adulto JovenRESUMEN
The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient's clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.