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1.
Am J Med Genet A ; 191(5): 1412-1417, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36863699

RESUMO

We report three unrelated individuals, each exposed to maternal autoantibodies during gestation and found to have elevated very long-chain fatty acids (VLCFAs) in the newborn period after screening positive by California newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD). Two probands presented with clinical and laboratory features of neonatal lupus erythematosus (NLE); the third had features suggestive of NLE and a known maternal history of Sjogren's syndrome and rheumatoid arthritis. In all three individuals, subsequent biochemical and molecular evaluation for primary and secondary peroxisomal disorders was nondiagnostic with normalization of VLCFAs by 15 months of age. These cases add to the expanding differential diagnosis to consider in newborns who screen positive for ALD via elevated C26:0-lysophosphatidylcholine. Though the pathophysiology of how transplacental maternal anti-Ro antibodies damage fetal tissue is not well-understood, we postulate that the VLCFA elevations reflect a systemic inflammatory response and secondary peroxisomal dysfunction that improves once maternal autoantibodies wane after birth. Additional evaluation of this phenomenon is warranted to better understand the intricate biochemical, clinical, and possible therapeutic overlap between autoimmunity, inflammation, peroxisomal dysfunction, and human disease.


Assuntos
Adrenoleucodistrofia , Lúpus Eritematoso Sistêmico , Humanos , Recém-Nascido , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/complicações , Triagem Neonatal , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/complicações , Autoanticorpos
2.
Am J Med Genet A ; 191(8): 2057-2063, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37144748

RESUMO

Zellweger spectrum disorder (ZSD) is a group of autosomal recessive disorders caused by biallelic pathogenic variants in any one of the 13 PEX genes essential for peroxisomal biogenesis. We report a cohort of nine infants who presented at birth with severe neonatal features suggestive of ZSD and found to be homozygous for a variant in PEX6 (NM_000287.4:c.1409G > C[p.Gly470Ala]). All were of Mixtec ancestry and identified by the California Newborn Screening (NBS) Program to have elevated C26:0-lysophosphatidylcholine but no reportable variants in ABCD1. The clinical and biochemical features of this cohort are described within. Gly470Ala may represent a founder variant in the Mixtec population of Central California. ZSD should be considered in patients who present at birth with severe hypotonia and enlarged fontanelles, especially in the setting of an abnormal NBS, Mixtec ancestry, or family history of infant death. There is a need to further characterize the natural history of ZSD, the Gly470Ala variant, and expand upon possible genotype-phenotype correlations.


Assuntos
Síndrome de Zellweger , Humanos , Recém-Nascido , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/genética , Síndrome de Zellweger/patologia , ATPases Associadas a Diversas Atividades Celulares/genética , Estudos de Associação Genética , Triagem Neonatal , Lisofosfatidilcolinas
3.
Pediatr Dev Pathol ; 26(4): 406-410, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37278357

RESUMO

Inherited syndromes of congenital enteropathy are rare, with many genetic causes described. Mutations of the AP1S1 gene results in the syndrome of intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (IDEDNIK, formerly in the medical literature as MEDNIK). The clinicopathologic features of the enteropathy in IDEDNIK syndrome have not been fully explored. We describe a female infant who presented with metabolic acidosis, lethargy, and 14 watery stools per day. In the intensive care unit she required parenteral nutrition. She was found to have a novel homozygous pathogenic variant in the AP1S1 gene c.186T>G (p.Y62*). Esophagogastroduodenoscopy and colonoscopy at 6 months of age were grossly normal. However, histologic sections of the duodenum showed mild villous blunting and enterocytes with cytoplasmic vacuoles. CD10 immunostaining highlighted the disrupted brush border. MOC31 immunostaining was wild-type with a membranous pattern of expression. Electron microscopy of the duodenum showed scattered enterocytes cells with shortened and disrupted apical microvilli. Although there is a mixed gap diarrhea and disrupted brush border, there are no significant inclusions typical of microvillus inclusion disease, nor tufted enterocytes typical of tufting enteropathy, making the clinical and histopathologic features for this syndrome unique.


Assuntos
Subunidades sigma do Complexo de Proteínas Adaptadoras , Síndromes de Malabsorção , Feminino , Humanos , Lactente , Complexo 1 de Proteínas Adaptadoras/genética , Subunidades sigma do Complexo de Proteínas Adaptadoras/genética , Diarreia/genética , Duodeno , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/genética , Síndromes de Malabsorção/metabolismo , Mutação , Síndrome
4.
Am J Med Genet A ; 188(11): 3358-3363, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36053530

RESUMO

RERE-related disorders, also known as Neurodevelopmental Disorders with or without Anomalies of the Brain, Eye, or Heart (NEDBEH), are caused by heterozygous pathogenic variants in the arginine-glutamic acid dipeptide repeats gene (RERE). Up-to-date, 20 cases have been reported with the core characteristics of developmental delay, intellectual disability, and/or autism spectrum disorder. Here, we describe three additional cases. In the first case, the patient was found to have a previously reported de novo missense variant; her clinical findings of global developmental delay, intellectual disability, autism spectrum disorder, vision abnormalities, musculoskeletal anomalies, dysmorphic facial features, and a congenital heart defect strengthen existing genotype-phenotype correlations. We also describe the first inherited variant in RERE, found in a patient (case 2) with developmental delay, autism, and hyperopia and his mother (case 3) with ADHD, myopia, and history of mild speech delay. Lastly, by summarizing the clinical features presented in the 23 cases now reported, we provide an updated review of the literature.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Anormalidades Musculoesqueléticas , Transtornos do Neurodesenvolvimento , Arginina/genética , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Variação Biológica da População , Proteínas de Transporte/genética , Dipeptídeos/genética , Feminino , Ácido Glutâmico/genética , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Fenótipo
5.
Am J Med Genet A ; 188(8): 2315-2324, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35633299

RESUMO

While combined pediatrics and medical genetics and genomics residency programs are growing in number and applicants, there are still workforce shortages within the medical genetics field. Medical students would benefit from additional information on the training pathways and insight into the application process itself. Program Directors of combined pediatrics and medical genetics and genomics residency programs were surveyed to characterize factors that influence interview selection and rank list decisions, application logistics, recruitment, and training pathways. When evaluating applicants, representatives from both pediatrics and medical genetics are involved in the screening process. Additionally, both groups value prior research experience, but do not have a clear preference for a particular subcategory or domain of research. Most program directors think that all currently-available training pathways can provide optimal training. Further action is needed to provide medical students with the knowledge to make more informed decisions about their career and medical school advisors with objective data to counsel students. There was support among program directors to initiate consideration of creating a pathway for medical students to match directly into a medical genetics and genomics residency.


Assuntos
Genética Médica , Internato e Residência , Estudantes de Medicina , Criança , Genômica , Humanos , Inquéritos e Questionários
6.
Genet Med ; 21(1): 81-88, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29899502

RESUMO

PURPOSE: Data sharing between clinicians, laboratories, and patients is essential for improvements in genomic medicine, but obtaining consent for individual-level data sharing is often hindered by a lack of time and resources. To address this issue, the Clinical Genome Resource (ClinGen) developed tools to facilitate consent, including a one-page consent form and online supplemental video with information on key topics, such as risks and benefits of data sharing. METHODS: To determine whether the consent form and video accurately conveyed key data sharing concepts, we surveyed 5,162 members of the general public. We measured comprehension at baseline, after reading the form and watching the video. Additionally, we assessed participants' attitudes toward genomic data sharing. RESULTS: Participants' performance on comprehension questions significantly improved over baseline after reading the form and continued to improve after watching the video. CONCLUSION: Results suggest reading the form alone provided participants with important knowledge regarding broad data sharing, and watching the video allowed for broader comprehension. These materials are now available at http://www.clinicalgenome.org/share . These resources will provide patients a straightforward way to share their genetic and health information, and improve the scientific community's access to data generated through routine healthcare.


Assuntos
Genética Médica/tendências , Genômica , Disseminação de Informação , Adulto , Feminino , Humanos , Consentimento Livre e Esclarecido , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
7.
Genet Med ; 21(4): 987-993, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30181607

RESUMO

The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.


Assuntos
Bases de Dados Genéticas , Genética Médica/tendências , Genoma Humano/genética , Genômica/tendências , Variação Genética/genética , Humanos , Disseminação de Informação , Medicina de Precisão
8.
Genet Med ; 18(12): 1258-1268, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27124788

RESUMO

PURPOSE: Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research. METHODS: We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability. RESULTS: We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders. CONCLUSION: The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Testes Genéticos , Variação Genética , Genômica , Exoma/genética , Doenças Genéticas Inatas/patologia , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Medicina de Precisão
10.
J Investig Med High Impact Case Rep ; 12: 23247096241267154, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39143735

RESUMO

Here, we report an individual, eventually diagnosed with HMG-CoA synthase deficiency, who presented with a cyclic vomiting phenotype. HMG-CoA synthase deficiency is a rare disorder affecting ketone body synthesis in which affected individuals typically present at a young age with hypoketotic hypoglycemia, lethargy, encephalopathy, and hepatomegaly, usually triggered by catabolism (e.g., infection or prolonged fasting). This individual presented with recurrent episodes of vomiting and lethargy, often associated with hypoglycemia or hyperglycemia, at 3 years of age. Metabolic labs revealed nonspecific abnormalities in her urine organic acids (showing mild elevation of dicarboxylic acids with relatively low excretion of ketones) and a normal acylcarnitine profile. Given her clinical presentation, as well as a normal upper gastrointestinal series, esophagogastroduodenoscopy with biopsies, and abdominal ultrasound, she was diagnosed with cyclic vomiting syndrome at 3 years of age. Molecular testing completed at 7 years of age revealed a previously reported pathogenic sequence variant (c.1016+1G>A) and a novel likely pathogenic deletion (1.57 kB deletion, including exon 1) within HMGCS2 consistent with HMG-CoA synthase deficiency. This individual's presentation, mimicking cyclic vomiting syndrome, widens the clinical spectrum of HMG-CoA synthase deficiency. In addition, this case highlights the importance of molecular genetic testing in such presentations, as this rare disorder lacks specific metabolic markers.


Assuntos
Hidroximetilglutaril-CoA Sintase , Vômito , Humanos , Vômito/etiologia , Feminino , Hidroximetilglutaril-CoA Sintase/genética , Hidroximetilglutaril-CoA Sintase/deficiência , Pré-Escolar , Biomarcadores/urina , Biomarcadores/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/complicações , Diagnóstico Diferencial , Acetil-CoA C-Acetiltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos
11.
Genes (Basel) ; 15(7)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-39062617

RESUMO

The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions beyond X-ALD that can also result in elevated C26:0-LPC by NBS. We describe the biochemical, molecular, and clinical characteristics of nine patients from two metabolic centers in California who screened positive by NBS for elevated C26:0-LPC between 2016 and 2022 and were ultimately diagnosed with a genetic condition other than X-ALD. Seven individuals were diagnosed with Zellweger spectrum disorder (ZSD) due to biallelic variants in PEX genes. One male was diagnosed with Klinefelter syndrome and one female was found to have an X chromosome contiguous gene deletion syndrome after the identification of a heterozygous VUS and hemizygous VUS variant in ABCD1, respectively. Patients with ZSD had significantly higher first- and second-tier C26:0-LPC levels compared to the two non-ZSD cases. Identification of children with ZSD and atypical patterns of ABCD1 variants is a secondary benefit of NBS for X-ALD, leading to earlier diagnosis, prompt therapeutic initiation, and more accurate genetic counseling. As screening for X-ALD continues via the measurement of C26:0-LPC, our knowledge of additional genetic conditions associated with elevated C26:0-LPC will continue to advance, allowing for increased recognition of other genetic disorders for which early intervention is warranted.


Assuntos
Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP , Adrenoleucodistrofia , Triagem Neonatal , Humanos , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/diagnóstico , Masculino , Feminino , Recém-Nascido , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Síndrome de Zellweger/genética , Síndrome de Zellweger/diagnóstico , California , Testes Genéticos/métodos
12.
Artigo em Inglês | MEDLINE | ID: mdl-29437798

RESUMO

Data sharing between laboratories, clinicians, researchers, and patients is essential for improvements and standardization in genomic medicine; encouraging genomic data sharing (GDS) is a key activity of the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen). The ClinGen initiative is dedicated to evaluating the clinical relevance of genes and variants for use in precision medicine and research. Currently, data originating from each of the aforementioned stakeholder groups is represented in ClinVar, a publicly available repository of genomic variation, and its relationship to human health hosted by the National Center for Biotechnology Information at the NIH. Although policies such as the 2014 NIH GDS policy are clear regarding the mandate for informed consent for broad data sharing from research participants, no clear guidance exists on the level of consent appropriate for the sharing of information obtained through clinical testing to advance knowledge. ClinGen has collaborated with ClinVar and the National Human Genome Research Institute to develop points to consider for clinical laboratories on sharing de-identified variant-level data in light of both the NIH GDS policy and the recent updates to the Common Rule. We propose specific data elements from interpreted genomic variants that are appropriate for submission to ClinVar when direct patient consent was not sought and describe situations in which obtaining informed consent is recommended.


Assuntos
Bases de Dados Genéticas , Testes Genéticos , Disseminação de Informação , Mutação/genética , Genômica , Humanos , Consentimento Livre e Esclarecido
13.
Curr Protoc Hum Genet ; 89: 8.16.1-8.16.23, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27037489

RESUMO

ClinVar is a freely accessible, public archive of reports of the relationships among genomic variants and phenotypes. To facilitate evaluation of the clinical significance of each variant, ClinVar aggregates submissions of the same variant, displays supporting data from each submission, and determines if the submitted clinical interpretations are conflicting or concordant. The unit describes how to (1) identify sequence and structural variants of interest in ClinVar by multiple searching approaches, including Variation Viewer and (2) understand the display of submissions to ClinVar and the evidence supporting each interpretation. By following this protocol, ClinVar users will be able to learn how to incorporate the wealth of resources and knowledge in ClinVar into variant curation and interpretation.


Assuntos
Bases de Dados Genéticas , Variação Genética , Genoma Humano , Humanos
14.
Curr Genet Med Rep ; 2(4): 223-241, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25401053

RESUMO

Genetic testing is becoming more common and more powerful by the day. The costs of the underlying DNA sequencing technology are plummeting, making it likely that tests based on it will become even more pervasive. The use of tests to determine DNA sequence to help make clinical decisions is here to stay. DNA sequencing is also finding new uses in forensics, determination of ancestry, understanding the history and genetic lineages of human populations and many other applications.

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