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Native American myopathy (NAM, also known as STAC3 disorder) (OMIM 255995) is an ultra-rare genetic disease impacting multiple body systems. The quality of life and caregiver burden associated with this condition remain poorly characterized. In this study, the Pediatric Quality of Life Inventory and a survey comprised of de novo questions concerning genetic testing, counseling, and caregiver burden were employed to investigate the health-related quality of life (HRQoL) in patients and caregivers with NAM. Study findings uncovered a concerning trend: patients with NAM experienced a notable decline in HRQoL, with reasons that warrant further investigation. Particularly striking was the downturn observed during the transition from adolescence to adulthood-across Physical, Social, and Emotional Functioning domains. Taken together, this study has elucidated novel insights into the impact of NAM, and areas of concern to improve HRQoL have subsequently been highlighted.
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Strong linear relationships between their Ceq-Os-Os-Ceq dihedral angles and their Os-Os bond distances in diosmium sawhorse complexes Os2(u-O2CR)2(CO)4L2 (L = CO and/or PR3) form two trendlines depending upon the presence or absence of terminal phosphines. These trends appear unrelated to the basicity of the bridging ligand or the number of phosphines. The mathematical derivation of the relationship between the O-Os-Os-O dihedral angle and the Os-Os bond distance shows how the other geometric parameters affect this relationship. Optimized density functional theory (DFT) structures reveal a similar strong linear correlation, where more electron-donating ligands render shorter Os-Os bond distances and larger dihedral angles, but these results form a single trendline. Computational scans of individual parameters show that the Os-Os bond responds strongly to changes in the dihedral angles, but the dihedral angles only respond weakly to changes in the Os-Os bond distance because the Os-Os-O bond angle links and modifies their direct coupling. Solid-state analysis of their structures, including DFT geometry optimizations, shows that phosphines protect the Os-Os bond distance from packing influences along the Os-Os axis, while in complexes without phosphines, packing compresses the Os-Os bond and the weak dihedral responses create the second trendline.
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Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.
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Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Proteínas Ativadoras de GTPase/genética , Hipotonia Muscular/etiologia , Mutação , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/etiologia , Espasmos Infantis/etiologia , Alelos , Movimento Celular , Proliferação de Células , Pré-Escolar , Família , Transtornos da Alimentação e da Ingestão de Alimentos/patologia , Feminino , Humanos , Lactente , Masculino , Hipotonia Muscular/patologia , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Espasmos Infantis/patologiaRESUMO
Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (â¼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.
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Neoplasias da Mama/diagnóstico , Testes Genéticos/estatística & dados numéricos , Perda Auditiva/diagnóstico , Doenças Metabólicas/diagnóstico , Síndrome Oculocerebrorrenal/diagnóstico , Neoplasias Ovarianas/diagnóstico , Neoplasias da Mama/genética , Pré-Escolar , Feminino , Genoma Humano , Perda Auditiva/genética , Heterozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Triagem Neonatal , North Carolina , Síndrome Oculocerebrorrenal/genética , Neoplasias Ovarianas/genética , Saúde Pública/métodos , Sequenciamento do ExomaRESUMO
Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.
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Iduronato Sulfatase , Mucopolissacaridose II , Criança , Humanos , Recém-Nascido , Estados Unidos , Mucopolissacaridose II/diagnóstico , Mucopolissacaridose II/genética , Triagem Neonatal , Ácido Idurônico , Iduronato Sulfatase/uso terapêutico , Glicosaminoglicanos , Terapia de Reposição de Enzimas/métodosRESUMO
Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.
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Anormalidades Múltiplas , Doenças Hematológicas , Doenças Vestibulares , Gravidez , Feminino , Humanos , Lactente , Anormalidades Múltiplas/genética , Face/anormalidades , Doenças Hematológicas/genética , Doenças Vestibulares/genética , Fenótipo , Histona Desmetilases/genéticaRESUMO
Importance: Genomic testing in infancy guides medical decisions and can improve health outcomes. However, it is unclear whether genomic sequencing or a targeted neonatal gene-sequencing test provides comparable molecular diagnostic yields and times to return of results. Objective: To compare outcomes of genomic sequencing with those of a targeted neonatal gene-sequencing test. Design, Setting, and Participants: The Genomic Medicine for Ill Neonates and Infants (GEMINI) study was a prospective, comparative, multicenter study of 400 hospitalized infants younger than 1 year of age (proband) and their parents, when available, suspected of having a genetic disorder. The study was conducted at 6 US hospitals from June 2019 to November 2021. Exposure: Enrolled participants underwent simultaneous testing with genomic sequencing and a targeted neonatal gene-sequencing test. Each laboratory performed an independent interpretation of variants guided by knowledge of the patient's phenotype and returned results to the clinical care team. Change in clinical management, therapies offered, and redirection of care was provided to families based on genetic findings from either platform. Main Outcomes and Measures: Primary end points were molecular diagnostic yield (participants with ≥1 pathogenic variant or variant of unknown significance), time to return of results, and clinical utility (changes in patient care). Results: A molecular diagnostic variant was identified in 51% of participants (n = 204; 297 variants identified with 134 being novel). Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI, 23%-32%) with the targeted gene-sequencing test. Genomic sequencing did not report 19 variants found by the targeted neonatal gene-sequencing test; the targeted gene-sequencing test did not report 164 variants identified by genomic sequencing as diagnostic. Variants unidentified by the targeted genomic-sequencing test included structural variants longer than 1 kilobase (25.1%) and genes excluded from the test (24.6%) (McNemar odds ratio, 8.6 [95% CI, 5.4-14.7]). Variant interpretation by laboratories differed by 43%. Median time to return of results was 6.1 days for genomic sequencing and 4.2 days for the targeted genomic-sequencing test; for urgent cases (n = 107) the time was 3.3 days for genomic sequencing and 4.0 days for the targeted gene-sequencing test. Changes in clinical care affected 19% of participants, and 76% of clinicians viewed genomic testing as useful or very useful in clinical decision-making, irrespective of a diagnosis. Conclusions and Relevance: The molecular diagnostic yield for genomic sequencing was higher than a targeted neonatal gene-sequencing test, but the time to return of routine results was slower. Interlaboratory variant interpretation contributes to differences in molecular diagnostic yield and may have important consequences for clinical management.
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Doenças Genéticas Inatas , Testes Genéticos , Triagem Neonatal , Análise de Sequência de DNA , Sequenciamento Completo do Genoma , Tomada de Decisão Clínica/métodos , Perfil Genético , Genômica , Estudos Prospectivos , Testes Genéticos/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Recém-Nascido , Triagem Neonatal/métodos , Lactente , Análise de Sequência de DNA/métodos , MutaçãoRESUMO
The mechanism for the CO substitution reaction involving the diosmium carbonyl sawhorse complex Os2(µ-O2CH)2(CO)6, which contains an Os-Os single bond, two axial CO ligands, and four equatorial CO ligands, was investigated experimentally and theoretically. Kinetic measurements show 13CO axial substitution proceeding by a dissociative reaction that is first-order in the complex and zero-order in 13CO but with an unexpectedly negative entropy of activation. The corresponding electronic structure calculations yield an enthalpy of activation for axial CO dissociation that is much larger than that determined by the kinetic experiments, but in agreement with the complex's stability with respect to CO loss. Additional calculations yield a dissociative interchange transition state whose free energy, enthalpy, and entropy of activation are in good agreement with those obtained from the kinetic measurements for the apparently dissociative substitution. These results point to an exchange reaction mechanism that is surprisingly close to the poorly understood transition from a dissociative mechanism with a CO-loss intermediate to a dissociative interchange mechanism with a transition state involving both the entering and the leaving COs. The key to explain these findings is provided by the vibrational analysis, which shows very low energy wagging motions for the axial COs. Thus, the incoming CO only displaces the outgoing CO when the complex has an outgoing CO near the wag's turning point. This dissociative interchange mechanism predicted by the calculation explains the unexpected combination of kinetics and stability characteristics. Kinetics reveals that the reaction is first-order in the Os dimer with a negative Eyring entropy, while a stability study shows that the Os dimer's decomposition rate is several orders of magnitude slower than CO exchange.
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PURPOSE: To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®). METHODS: A team of clinical genetics educators performed an analysis of the representation of genetics content on a robust sample of recent Step 1, Step 2 Clinical Knowledge (CK), and Step 3 examination forms. The content of each question was mapped to curriculum recommendations from the peer reviewed Association of Professors of Human and Medical Genetics white paper, Medical School Core Curriculum in Genetics, and the USMLE Content Outline. RESULTS: The committee identified 13.4%, 10.4%, and 4.4% of Steps 1, 2 and 3 respectively, as having genetics content. The genetics content of the exams became less pertinent to the questions from Step 1 to 3, with decreasing genetics content by exam and increasing percentages of questions identified as having genetics content in the distractors only. CONCLUSION: The current distribution of genetics in USMLE licensing examinations reflects traditional curricular approaches with genetics as a basic science course in the early years of medical school and de-emphasizes clinical relevance of the field. These observations support the notion that further integration is required to move genetics into the clinical curriculum of medical schools and the clinical content of USMLE Step exams.
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Educação de Graduação em Medicina , Educação Médica , Competência Clínica , Currículo , Avaliação Educacional , Genômica , Humanos , Licenciamento em Medicina , Estados UnidosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: We investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing. METHODS: ES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions. RESULTS: In 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition. CONCLUSION: ES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.
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Exoma , Ultrassonografia Pré-Natal , Exoma/genética , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Diagnóstico Pré-Natal , Sequenciamento do ExomaRESUMO
OBJECTIVE: This study aimed to understand parental decisions, perspectives, values, and beliefs on next generation sequencing in the newborn period (NGS-NBS) to inform the development of a decision aid to support parental decision making in the North Carolina Newborn Exome Sequencing for Universal Screening study. METHODS: We conducted dyadic interviews with 66 current or expectant parents (33 couples) to understand overall decisions about NGS-NBS and reasons for and against learning NGS-NBS results differing by age of onset and medical actionability. Audio recordings were transcribed, coded, and analyzed using qualitative framework analyses. RESULTS: Favorable views of NGS-NBS included benefits of early intervention, preparedness, child autonomy, and altruism. Unfavorable views were the potential negative effects from early intervention, psychosocial harm, and religious beliefs. Parents universally reported quality of life as important. CONCLUSION: Interviews elucidated what is important in deciding to have NGS-NBS. Understanding parental perspectives, values, and beliefs and integrating evidence-based findings into a parent-centric decision aid provides value and support in making decisions related to NGS-NBS, where there is no clear course of action.
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Técnicas de Apoio para a Decisão , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Triagem Neonatal/métodos , Pais/psicologia , Adulto , Características da Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Recém-Nascido , North Carolina , Pesquisa QualitativaRESUMO
OBJECTIVE: To evaluate the performance of a 2-tiered newborn screening method for mucopolysaccharidosis type I (MPS I) in North Carolina. STUDY DESIGN: The screening algorithm included a flow injection analysis-tandem mass spectrometry assay as a first-tier screening method to measure α-L-iduronidase (IDUA) enzyme activity and Sanger sequencing of the IDUA gene on dried blood spots as a second-tier assay. The screening algorithm was revised to incorporate the Collaborative Laboratory Integrated Reports, an analytical interpretive tool, to reduce the false-positive rate. A medical history, physical examination, IDUA activity, and urinary glycosaminoglycan (GAG) analysis were obtained on all screen-positive infants. RESULTS: A total of 62 734 specimens were screened with 54 screen-positive samples using a cut-off of 15% of daily mean IDUA activity. The implementation of Collaborative Laboratory Integrated Reports reduced the number of specimens that screened positive to 19 infants. Of the infants identified as screen-positive, 1 had elevated urinary GAGs and a homozygous pathogenic variant associated with the severe form of MPS I. All other screen-positive infants had normal urinary GAG analysis; 13 newborns had pseudodeficiency alleles, 3 newborns had variants of unknown significance, and 2 had heterozygous pathogenic variants. CONCLUSIONS: An infant with severe MPS I was identified and referred for a hematopoietic stem cell transplant. Newborn IDUA enzyme deficiency is common in North Carolina, but most are due to pseudodeficiency alleles in infants with normal urinary GAG analysis and no evidence of disease. The pilot study confirmed the need for second-tier testing to reduce the follow-up burden.
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Mucopolissacaridose I/diagnóstico , Triagem Neonatal , Algoritmos , Dermatan Sulfato/urina , Testes Genéticos , Variação Genética , Glicosaminoglicanos/urina , Heparitina Sulfato/urina , Humanos , Iduronidase/sangue , Iduronidase/genética , Recém-Nascido , Mucopolissacaridose I/genética , North Carolina , Encaminhamento e Consulta/estatística & dados numéricos , Análise de Sequência , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: To assess the performance of a standardized, age-based metric for scoring clinical actionability to evaluate conditions for inclusion in newborn screening and compare it with the results from other contemporary methods. STUDY DESIGN: The North Carolina Newborn Exome Sequencing for Universal Screening study developed an age-based, semiquantitative metric to assess the clinical actionability of gene-disease pairs and classify them with respect to age of onset or timing of interventions. This categorization was compared with the gold standard Recommended Uniform Screening Panel and other methods to evaluate gene-disease pairs for newborn genomic sequencing. RESULTS: We assessed 822 gene-disease pairs, enriched for pediatric onset of disease and suspected actionability. Of these, 466 were classified as having childhood onset and high actionability, analogous to conditions selected for the Recommended Uniform Screening Panel core panel. Another 245 were classified as having childhood onset and low to no actionability, 25 were classified as having adult onset and high actionability, 19 were classified as having adult onset and low to no actionability, and 67 were excluded due to controversial evidence and/or prenatal onset. CONCLUSIONS: This study describes a novel method to facilitate decisions about the potential use of genomic sequencing for newborn screening. These categories may assist parents and physicians in making informed decisions about the disclosure of results from voluntary genomic sequencing in children.
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Mapeamento Cromossômico/métodos , Doenças Genéticas Inatas/diagnóstico , Testes Genéticos/métodos , Triagem Neonatal/métodos , Análise de Sequência de DNA/métodos , Tomada de Decisão Compartilhada , Feminino , Doenças Genéticas Inatas/epidemiologia , Genoma Humano , Humanos , Recém-Nascido , Masculino , North Carolina , Sequenciamento do ExomaRESUMO
BACKGROUND: Newborn screening (NBS) occupies a unique space at the intersection of translational science and public health. As the only truly population-based public health program in the United States, NBS offers the promise of making the successes of translational medicine available to every infant with a rare disorder that is difficult to diagnose clinically, but for which strong evidence indicates that presymptomatic treatment will substantially improve outcomes. Realistic NBS policy requires data, but rare disorders face a special challenge: Screening cannot be done without supportive data, but adequate data cannot be collected in the absence of large-scale screening. The magnitude and scale of research to provide this expanse of data require working with public health programs, but most do not have the resources or mandate to conduct research. METHODS: To address this gap, we have established Early Check, a research program in partnership with a state NBS program. Early Check provides the infrastructure needed to identify conditions for which there have been significant advances in treatment potential, but require a large-scale, population-based study to test benefits and risks, demonstrate feasibility, and inform NBS policy. DISCUSSION: Our goal is to prove the benefits of a program that can, when compared with current models, accelerate understanding of diseases and treatments, reduce the time needed to consider inclusion of appropriate conditions in the standard NBS panel, and accelerate future research on new NBS conditions, including clinical trials for investigational interventions. TRIAL REGISTRATION: Clinicaltrials.gov registration # NCT03655223 . Registered on August 31, 2018.
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Síndrome do Cromossomo X Frágil/diagnóstico , Atrofia Muscular Espinal/diagnóstico , Triagem Neonatal , Saúde Pública , Pesquisa Translacional Biomédica , Diagnóstico Precoce , Feminino , Seguimentos , Síndrome do Cromossomo X Frágil/epidemiologia , Política de Saúde , Humanos , Recém-Nascido , Consentimento Livre e Esclarecido , Internet , Colaboração Intersetorial , Masculino , Atrofia Muscular Espinal/epidemiologia , North Carolina/epidemiologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Seleção de Pacientes , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Grupos de AutoajudaRESUMO
Newborn screening is a system that provides early identification and treatment of infants with disorders prior to permanent disability or death. A successful newborn screening program requires skilled effort, understanding, and collaboration by many individuals, from those collecting the blood spots to the child's primary care provider and family.
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Triagem Neonatal , Humanos , Recém-NascidoRESUMO
PurposeApplication of whole-exome and whole-genome sequencing is likely to increase in clinical practice, public health contexts, and research. We investigated how parental preference for acquiring information from genome-scale testing is influenced by the characteristics of non-medically actionable genetic disorders in children, as well as whether the preferences differed by gender and between African-American and white respondents.MethodsWe conducted a Web-based discrete-choice experiment with 1,289 parents of young children. Participants completed "choice tasks" based on pairs of profiles describing sequencing results for hypothetical genetic disorders, selected the profile in each pair that they believed represented the information that would be more important to know, and answered questions that measured their level of distress.ResultsKnowing the likelihood that the disorder would develop given a true-positive test result was most important to parents. Parents showed greater interest in learning sequencing results for disease profiles with more severe manifestations. This was associated with greater distress. Differences by gender and race reflected small differences in magnitude, but not direction.ConclusionParents preferred to learn results about genetic disorders with more severe manifestations, even when this knowledge was associated with increased distress. These results may help clinicians support parental decision making by revealing which types of sequencing results parents are interested in learning.
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Comportamento de Escolha , Tomada de Decisões , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Testes Genéticos , Pais/psicologia , Sequenciamento Completo do Genoma , Adulto , Idade de Início , Criança , Feminino , Doenças Genéticas Inatas/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Fenótipo , Inquéritos e QuestionáriosRESUMO
SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.
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Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Fenótipo , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fácies , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Padrões de Herança , Masculino , Polimorfismo de Nucleotídeo Único , Síndrome , Adulto JovemRESUMO
Genet Med 19 3, 294-296.
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Genética Médica/educação , Genômica/educação , Humanos , Laboratórios , Conselhos de Especialidade Profissional/normas , Estados UnidosRESUMO
PurposeWe investigated the diagnostic and clinical performance of exome sequencing in fetuses with sonographic abnormalities with normal karyotype and microarray and, in some cases, normal gene-specific sequencing.MethodsExome sequencing was performed on DNA from 15 anomalous fetuses and from the peripheral blood of their parents. Parents provided consent to be informed of diagnostic results in the fetus, medically actionable findings in the parents, and their identification as carrier couples for significant autosomal recessive conditions. We assessed the perceptions and understanding of exome sequencing using mixed methods in 15 mother-father dyads.ResultsIn seven (47%) of 15 fetuses, exome sequencing provided a diagnosis or possible diagnosis with identification of variants in the following genes: COL1A1, MUSK, KCTD1, RTTN, TMEM67, PIEZO1 and DYNC2H1. One additional case revealed a de novo nonsense mutation in a novel candidate gene (MAP4K4). The perceived likelihood that exome sequencing would explain the results (5.2 on a 10-point scale) was higher than the approximately 30% diagnostic yield discussed in pretest counseling.ConclusionExome sequencing had diagnostic utility in a highly select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy and variant interpretation must be addressed by highly tailored pre- and posttest genetic counseling.