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1.
Prenat Diagn ; 44(5): 586-594, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38558419

RESUMO

OBJECTIVES: To investigate the prenatal detection rate of mosaicism by SNP microarray analysis, in which an individual has not one, but two, complete genomes (sets of DNA) in their body, a normal biparental line with a Genome Wide Uniparental Disomy (GWUPD) cell line was used. METHODS: This study retrospectively examines the prenatal detection of GWUPD in a cohort of ∼90,000 prenatal specimens and ∼20,000 products of conceptions (POCs) that were studied by SNP microarray. RESULTS: In total, 25 cases of GWUPD were detected; 16 cases were detected prenatally with GWUPD (∼0.018%) and 9 POCs revealed GWUPD (0.045%). The nine POC specimens presented with placental abnormalities. The 12 amniotic fluid specimens were ascertained because of abnormal ultrasound findings. Nine of 12 pregnancies had findings consistent with Beckwith-Wiedemann syndrome or because of abnormal placentas. However, three pregnancies were detected with GWUPD of maternal origin, with less common findings and demonstrated maternal origin. Four other pregnancies showed GWUPD in a chorionic villus sample, but normal findings in amniotic fluid and apparently normal fetal development. CONCLUSIONS: This cohort with GWUPD mosaicism expands our understanding of GWUPD and has implications for prenatal care and counseling. Additional studies are necessary to understand the rarer maternal GWUPD.


Assuntos
Mosaicismo , Diagnóstico Pré-Natal , Dissomia Uniparental , Humanos , Feminino , Mosaicismo/embriologia , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Gravidez , Estudos Retrospectivos , Adulto , Diagnóstico Pré-Natal/métodos , Polimorfismo de Nucleotídeo Único , Estudos de Coortes
2.
Am J Med Genet A ; 191(6): 1639-1645, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36941760

RESUMO

The 6p25 deletion syndrome is a rare genetic disorder characterized by a wide spectrum of congenital anomalies. Ophthalmic abnormalities appear to be highly associated with the syndrome, although this relationship has not been well characterized to date. We conducted a systematic literature review to highlight the ocular features in patients with this deletion syndrome and describe a 7-month-old female who has a 6.07 MB 6p25.1p25.3 deletion and a 4.25 MB 17q25.3 duplication. Our patient presented with multiple congenital anomalies, including macrocephaly, frontal bossing, low set ears, tent-shaped mouth, saddle nose, flat midface, and hearing impairment. Her ophthalmic features included proptosis, down-slanting palpebral fissures, hypertelorism, nystagmus, bilateral posterior embryotoxon, and decentered and abnormally shaped pupils. A systematic review of the published cases with sufficient clinical eye descriptions included 63 cases with a confirmed 6p25 deletion. The most common eye findings observed were posterior embryotoxon, iris hypoplasia, corectopia, cornea opacity, and glaucoma.


Assuntos
Anormalidades do Olho , Glaucoma , Humanos , Feminino , Lactente , Deleção Cromossômica , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Glaucoma/genética , Síndrome , Cromossomos
3.
Cancer Genet ; 244: 11-20, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32087595

RESUMO

BACKGROUND: Genomic abnormalities in breast cancer have been described according to diverse conceptual frameworks, including histologic subtypes, clinical molecular subtypes, intrinsic DNA, RNA, and epigenetic profiles, and activated molecular pathways. METHODS: The Cancer Genomics Consortium (CGC) Breast Cancer Workgroup performed an evidence based literature review to summarize current knowledge of clinically significant genomic alterations in breast cancer using CGC levels of evidence. Targetable or disease-defining alterations were prioritized. RESULTS: We summarized genomic alterations in breast cancer within a framework of existing clinical tools for diagnosis, risk stratification, and therapeutic management. Using CGC levels of evidence, we catalog copy number profiles, gene expression profiles, and mutations in clinically significant genes. We also describe emerging molecular markers such as methylation profiling and immunotherapy biomarkers. CONCLUSION: A summary of currently available information on breast cancer genomics will enhance precision medicine by serving as an interpretive resource for clinical laboratory geneticists, providing a foundation for future practice guidelines, and identifying knowledge gaps to address in future research.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genômica/métodos , Mutação , Medicina de Precisão/tendências , Transcriptoma , Feminino , Humanos , Prognóstico
4.
Artigo em Inglês | MEDLINE | ID: mdl-30275001

RESUMO

Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants in SAMHD1, a gene associated with the recessive condition Aicardi-Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specific SAMHD1 variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Pré-Escolar , Exoma , Feminino , Predisposição Genética para Doença , Variação Genética/genética , Heterozigoto , Humanos , Mutação , Fenótipo , Estudos Retrospectivos , Proteína 1 com Domínio SAM e Domínio HD/genética , Proteína 1 com Domínio SAM e Domínio HD/fisiologia , Sequenciamento do Exoma/métodos
5.
Am J Clin Pathol ; 149(2): 135-147, 2018 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-29385416

RESUMO

OBJECTIVES: To develop and test an integrated approach to human epidermal growth factor receptor 2 (HER2) copy number analysis in breast cancer using in situ hybridization (ISH) and cytogenomic microarray (CMA). METHODS: CMA was performed on four clinical breast cancer samples with nonclassical patterns of HER2 ISH results. Integrated analysis was performed by correlating the data from pathology review, ISH, and CMA. RESULTS: Integrated analysis provided a more comprehensive view of the genomic copy number landscape that informed HER2 copy number analysis, but ISH provided essential data in all cases. CONCLUSIONS: CMA can be helpful for clarifying HER2 amplification status in breast cancer. However, uncertainties over tumor percentage, clonal heterogeneity, and varying ploidy levels present challenges for genomic methods such as CMA. Accurate interpretation of HER2 copy number by CMA requires correlation with the pathology and ISH data.


Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Variações do Número de Cópias de DNA , DNA de Neoplasias/análise , Hibridização in Situ Fluorescente , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Receptor ErbB-2/genética , Adulto , Feminino , Humanos , Pessoa de Meia-Idade
6.
Neurol Genet ; 4(1): e212, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29417091

RESUMO

OBJECTIVE: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). METHODS: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup. RESULTS: The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis. CONCLUSIONS: Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

7.
Circ Cardiovasc Genet ; 10(3)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28611029

RESUMO

BACKGROUND: The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset. METHODS AND RESULTS: We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.8% of cases and variants of uncertain significance in 34.5% of cases. Three patients harbored heterozygous nonsense or splice-site variants in the nucleoporin genes NUP37, NUP43, and NUP188, which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene SYNE1 in a child with severe dilated cardiomyopathy that underwent transplant, as well as in his affected father. To confirm a cardiovascular role for these candidate genes in vivo, we used morpholinos to reduce SYNE1, NUP37, and NUP43 gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a SYNE1 splice-site variant displayed changes in nuclear morphology and protein localization that are consistent with disruption of the nuclear envelope. CONCLUSIONS: These data expand the repertoire of pathogenic variants associated with cardiovascular disease and validate the diagnostic and research use of whole exome sequencing. We identify NUP37, NUP43, and NUP188 as novel candidate genes for cardiovascular disease, and suggest that dysfunction of the nuclear envelope may be an under-recognized component of inherited cardiac disease in some cases.


Assuntos
Doenças Cardiovasculares/diagnóstico , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Proteínas do Citoesqueleto , Bases de Dados Genéticas , Embrião não Mamífero/metabolismo , Variação Genética , Heterozigoto , Humanos , Lamina Tipo A/metabolismo , Morfolinos/metabolismo , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/antagonistas & inibidores , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Nucleares/metabolismo , Fenótipo , Interferência de RNA , Sítios de Splice de RNA/genética , Análise de Sequência de DNA , Sequenciamento do Exoma , Peixe-Zebra
8.
J Heart Valve Dis ; 26(5): 569-580, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-29762926

RESUMO

BACKGROUND: A genetic component to familial mitral valve prolapse (MVP) has been proposed for decades. Despite this, very few genes have been linked to MVP. Herein is described a four-generation pedigree with numerous individuals affected with severe MVP, some at strikingly young ages. METHODS: A detailed clinical evaluation performed on all affected family members demonstrated a spectrum of MVP morphologies and associated phenotypes. RESULTS: Linkage analysis failed to identify strong candidate loci, but revealed significant regions, which were investigated further using whole-exome sequencing of one of the severely affected family members. Whole-exome sequencing identified variants in this individual that fell within linkage analysis peak regions, but none was an obvious pathogenic candidate. Follow up segregation analysis of all exome-identified variants was performed to genotype other affected and unaffected individuals in the family, but no variants emerged as clear pathogenic candidates. Two notable variants of uncertain significance in candidate genes were identified: p.I1013S in PTPRJ at 11p11.2 and FLYWCH1 p.R540Q at 16p13.3. Neither gene has been previously linked to MVP in humans, although PTPRJ mutant mice display defects in endocardial cushions, which give rise to the cardiac valves. PTPRJ and FLYWCH1 expression was detected in adult human mitral valve cells, and in-silico analysis of these variants suggests they may be deleterious. However, neither variant segregated completely with all of the affected individuals in the family, particularly when 'affected' was broadly defined. CONCLUSIONS: While a contributory role for PTPRJ and FLYWCH1 in this family cannot be excluded, the study results underscored the difficulties involved in uncovering the genomic contribution to MVP, even in apparently Mendelian families.


Assuntos
Prolapso da Valva Mitral , Dedos de Zinco/genética , Adulto , Criança , Ecocardiografia/métodos , Saúde da Família , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Prolapso da Valva Mitral/diagnóstico , Prolapso da Valva Mitral/genética , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/genética , Sequenciamento do Exoma/métodos
9.
Int J Dev Neurosci ; 20(3-5): 407-19, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12175881

RESUMO

22q11 deletion syndrome (22qDS), also known as DiGeorge or velocardiofacial syndrome (DGS/VCFS), is a relatively common genetic anomaly that results in malformations of the heart, face and limbs. In addition, patients with 22qDS are at significant risk for psychiatric disorders as well, with one in four developing schizophrenia, and one in six developing major depressive disorders. Like several other deletion syndromes associated with psychiatric or cognitive problems, it has been difficult to determine which of the specific genes in this genomic region may mediate the syndrome. For example, patients with different genomic deletions within the 22q11 region have been found that have similar phenotypes, even though their deletions do not compromise the same set of genes. In this review, we discuss the individual genes found in the region of 22q11 that is commonly deleted in 22qDS patients, and the potential roles each of these genes may play in the syndrome. Although many of these genes are interesting candidates by themselves, we hypothesize that the full spectrum of anomalies associated with 22qDS may result from the combined result of disruptions to numerous genes within the region that are involved in similar developmental or cellular processes.


Assuntos
Cromossomos Humanos Par 22/genética , Transtorno Depressivo Maior/genética , Deficiências do Desenvolvimento/genética , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/genética , Mutação/genética , Esquizofrenia/genética , Animais , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/fisiopatologia , Criança , Mapeamento Cromossômico , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/fisiopatologia , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Genoma , Humanos , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia
10.
Mech Dev ; 111(1-2): 177-80, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11804793

RESUMO

RanBP1, a velocardiofacial syndrome/DiGeorge syndrome candidate gene, is expressed in the frontonasal processes, branchial arches, aortic arches, and limb buds. At these sites, RanBP1 apparently coincides with neural crest-derived mesenchymal cells. In addition, RanBP1 is expressed in the forebrain as well as in hindbrain regions previously associated with crest-derived mesenchymal cells.


Assuntos
Epitélio/embriologia , Mesoderma , Proteínas Nucleares/genética , Proteína ran de Ligação ao GTP/genética , Animais , Aorta/embriologia , Síndrome de DiGeorge/genética , Indução Embrionária/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Botões de Extremidades , Camundongos , Camundongos Endogâmicos ICR , Proteínas Nucleares/metabolismo , Proteína ran de Ligação ao GTP/metabolismo
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