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1.
Genet Med ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31417191

RESUMO

PURPOSE: Access to genetics health-care services is often complicated by the distance to hospitals, workforce shortages, and insurance coverage. Despite technological advances and decreasing costs of genetic sequencing, the benefits of personalized medicine may be inaccessible to many patients. To assess potential disparities in care, we examined the genetics workforce in California and geographical issues that people encounter in seeking care. METHODS: Data on all board-certified genetics providers were analyzed including medical geneticists (MGs) and genetic counselors (GCs) in California. To assess distance traveled for care, we computed the distance patients traveled for n = 288 visits to University of California-San Francisco (UCSF) Medical Genetics. We performed geographic optimization to minimize the distance to genetics providers. RESULTS: The provider-to-patient ratio in California is 1:330,000 for MGs, 1:100,000 for GCs, and 1:1,520,000 for biochemical MGs. Genetics providers are concentrated in major metropolitan areas in California. People travel up to 386 miles for genetics care within the state (mean = 76.6 miles). CONCLUSION: There are substantial geographic barriers to genetics care that could increase disparities. Our findings highlight a challenging genetics workforce shortage. The shortage may be even greater due to care subspecialization or lack of full-time equivalency and staffing. We are currently promoting efforts to increase remote health-care options, training, and modified models of care.

2.
Mol Cancer Ther ; 18(9): 1565-1576, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270152

RESUMO

Amplification of the epidermal growth factor receptor gene (EGFR) represents one of the most commonly observed genetic lesions in glioblastoma (GBM); however, therapies targeting this signaling pathway have failed clinically. Here, using human tumors, primary patient-derived xenografts (PDX), and a murine model for GBM, we demonstrate that EGFR inhibition leads to increased invasion of tumor cells. Further, EGFR inhibitor-treated GBM demonstrates altered oxidative stress, with increased lipid peroxidation, and generation of toxic lipid peroxidation products. A tumor cell subpopulation with elevated aldehyde dehydrogenase (ALDH) levels was determined to comprise a significant proportion of the invasive cells observed in EGFR inhibitor-treated GBM. Our analysis of the ALDH1A1 protein in newly diagnosed GBM revealed detectable ALDH1A1 expression in 69% (35/51) of the cases, but in relatively low percentages of tumor cells. Analysis of paired human GBM before and after EGFR inhibitor therapy showed an increase in ALDH1A1 expression in EGFR-amplified tumors (P < 0.05, n = 13 tumor pairs), and in murine GBM ALDH1A1-high clones were more resistant to EGFR inhibition than ALDH1A1-low clones. Our data identify ALDH levels as a biomarker of GBM cells with high invasive potential, altered oxidative stress, and resistance to EGFR inhibition, and reveal a therapeutic target whose inhibition should limit GBM invasion.

3.
Eur Respir J ; 54(2)2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31151956

RESUMO

Rare variants in the T-box transcription factor 4 gene (TBX4) have recently been recognised as an emerging cause of paediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH.We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next-generation sequencing and copy number variation arrays.Variants included six 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and two required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling.TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.

4.
Cleft Palate Craniofac J ; : 1055665619858257, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248274

RESUMO

Floating-Harbor syndrome (FHS) is a rare genetic disorder caused by heterozygous mutations in the Snf2-related CREBBP activator protein (SRCAP) gene. The syndrome is characterized by proportional short stature, delayed bone maturation, delayed speech development, and facial dysmorphism. Submucous cleft palate and cleft lip have been reported in FHS, but to our knowledge orofacial clefting in this condition has not been assessed in detail. Here, we report on a case of bilateral cleft lip in a patient with FHS confirmed by exome sequencing.

5.
Am J Med Genet A ; 179(7): 1246-1252, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31039288

RESUMO

Schimke immunoosseous dysplasia (SIOD) is a multisystemic condition characterized by early arteriosclerosis and progressive renal insufficiency, among other features. Many SIOD patients have severe, migraine-like headaches, transient neurologic attacks, or cerebral ischemic events. Cerebral events could be exacerbated or precipitated by hypertension, and it is unclear how these are related to arteriosclerotic changes as dyslipidemia is also a feature of SIOD. The correlation between hypercholesterolemia and cardiovascular risk in SIOD is unclear. Also, the etiology and management of headaches is not well characterized. Here we report our clinical observations in the management of SIOD in a patient who was diagnosed in school age despite early signs and symptoms. We describe biallelic variants, including a previously unreported c.1931G>A (p.Arg644Gln) variant in SMARCAL1. We specifically investigated whether migraine-like headaches and progressive nephropathy may be related to blood pressure dysregulation. We found a correlation between tighter blood pressure regulation using ambulatory blood pressure monitoring and a subjective decrease in headache symptoms. We discuss blood pressure medication management in SIOD. We also characterize dyslipidemia relative to atherosclerosis risks and provide new management strategies to consider for optimizing care.

6.
Am J Med Genet A ; 179(6): 966-977, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30920161

RESUMO

Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p = .0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

8.
Pediatrics ; 143(Suppl 1): S22-S26, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30600267

RESUMO

BACKGROUND: Genetic data have the potential to impact patient care significantly. In primary care and in the ICU, patients are undergoing genetic testing. Genetics is also transforming cancer care and undiagnosed diseases. Optimal personalized medicine relies on the understanding of disease penetrance. In this article, I examine the complexity of penetrance. METHODS: In this article, I assess how variable penetrance can be seen with many diseases, including those of different modes of inheritance, and how genomic testing is being applied effectively for many diseases. In this article, I also identify challenges in the field, including the interpretation of gene variants. RESULTS: Using advancing bioinformatics and detailed phenotypic assessment, we can increase the yield of genomic testing, particularly for highly penetrant conditions. The technologies are useful and applicable to different medical situations. CONCLUSIONS: There are now effective genome diagnostics for many diseases. However, the best personalized application of these data still requires skilled interpretation.

9.
Brain Pathol ; 2018 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-30051528

RESUMO

Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.

10.
Mol Genet Genomic Med ; 6(5): 722-727, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30047259

RESUMO

BACKGROUND: When a family encounters the loss of a child early in life, extensive genetic testing of the affected neonate is sometimes not performed or not possible. However, the increasing availability of genomic sequencing may allow for direct application to families in cases where there is a condition inherited from parental gene(s). When neonatal testing is not possible, it is feasible to perform family testing as long as there is optimal interpretation of the genomic information. Here, we present an example of a healthy adult woman with a history of recurrent male neonatal losses due to severe respiratory distress who presented to Medical Genetics for evaluation. A family history of additional male neonatal loss was present, suggesting a potential inherited genetic etiology. METHODS: Although there was no DNA available from the neonates, by performing exome sequencing on the healthy adult woman, we found a missense variant in MTM1 as a potential candidate, which was deemed pathogenic based on multiple criteria including past report. RESULTS: By performing an analysis of all known MTM1-disease associated mutations and control population variation, we can also better infer the effects of missense variations on MTM1, as not all variants are truncating. MTM1-X-linked myotubular myopathy is a condition that leads to male perinatal respiratory failure and a high risk for early mortality. CONCLUSIONS: The application of genetic testing in the healthy population here highlights the broader utility of genomic sequencing in evaluating unexplained recurrent neonatal loss, especially when genetic testing is not available on the affected neonates.

11.
JCI Insight ; 3(2)2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29367466

RESUMO

Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene was confirmed (Hnrnpa1ct). Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation. Hnrnpa1ct/ct homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of Hnrnpa1 expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of HNRNPA1 were detected in human CHDs. These findings suggest a role of Hnrnpa1 in embryonic heart development in mice and humans.

12.
J Pediatr ; 189: 222-226.e1, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28947054

RESUMO

We present cases of 3 children diagnosed with the same genetic condition, Gitelman syndrome, at different stages using various genetic methods: panel testing, targeted single gene sequencing, and exome sequencing. We discuss the advantages and disadvantages of each method and review the potential of genomic sequencing for early disease detection.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Síndrome de Gitelman/diagnóstico , Análise de Sequência de DNA/métodos , Adolescente , Criança , Pré-Escolar , Diagnóstico Precoce , Testes Genéticos/métodos , Humanos , Masculino
13.
Ocul Oncol Pathol ; 3(2): 122-128, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28868283

RESUMO

PURPOSE: Uveal ganglioneuroma is a rare tumor that usually occurs in association with neurofibromatosis type 1. Here, we present a rare case of a uveal ganglioneuroma leading to a diagnosis of the tumor predisposition condition Cowden syndrome. PROCEDURES: A 5-year-old girl with unilateral refractory glaucoma secondary to diffuse iris and choroidal thickening developed a blind, painful eye. Enucleation was performed, and histopathology revealed infiltration of the entire uveal tract by neoplastic spindle cells containing admixed ganglion cells diagnostic of uveal ganglioneuroma. Targeted next-generation sequencing of 510 cancer-associated genes was performed on tumor tissue and peripheral blood. RESULTS: A germline nonsense mutation in the PTEN gene was found, accompanied by loss of heterozygosity in the tumor. A diagnosis of Cowden syndrome was made, for which the family sought genetic counseling and initiated the recommended cancer screening. CONCLUSIONS: A novel association is found between uveal ganglioneuroma and Cowden syndrome, emphasizing the value of genetic tissue testing in managing patients with rare ocular tumors.

14.
Clin Neuropathol ; 36(5): 213-221, 2017 Sep/Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28699883

RESUMO

Familial melanoma-astrocytoma syndrome is a tumor predisposition syndrome caused by inactivating germline alteration of the CDKN2A tumor suppressor gene on chromosome 9p21. While some families with germline CDKN2A mutations are prone to development of just melanomas, other families develop both melanomas, astrocytomas, and occasionally other nervous-system neoplasms including peripheral nerve sheath tumors and meningiomas. The histologic spectrum of the astrocytomas that arise as part of this syndrome is not well described, nor are the additional genetic alterations that drive these astrocytomas apart from the germline CDKN2A inactivation. Herein, we report the case of a young man with synchronous development of a pleomorphic xanthoastrocytoma, diffuse astrocytoma, and paraspinal mass radiographically consistent with a peripheral nerve sheath tumor. His paternal family history is significant for melanoma, glioblastoma, and oral squamous cell carcinoma. Genomic profiling revealed that he harbors a heterozygous deletion in the germline of chromosome 9p21.3 encompassing the CDKN2A and CDKN2B tumor suppressor genes. Both the pleomorphic xanthoastrocytoma and diffuse astrocytoma were found to have homozygous deletion of CDKN2A/B due to somatic loss of the other copy of chromosome 9p containing the remaining intact alleles. Additional somatic alterations included BRAF p.V600E mutation in the pleomorphic xanthoastrocytoma and PTPN11, ATRX, and NF1 mutations in the diffuse astrocytoma. The presence of germline CDKN2A/B inactivation together with the presence of multiple anatomically, histologically, and genetically distinct astrocytic neoplasms, both with accompanying somatic loss of heterozygosity for the CDKN2A/B deletion, led to a diagnosis of familial melanoma-astrocytoma syndrome. This remarkable case illustrates the histologic and genetic diversity that astrocytomas arising as part of this rare glioma predisposition syndrome can demonstrate.
.


Assuntos
Astrocitoma/genética , Astrocitoma/patologia , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p18/genética , Melanoma/genética , Melanoma/patologia , Neoplasias do Sistema Nervoso/genética , Neoplasias do Sistema Nervoso/patologia , Humanos , Masculino , Linhagem , Adulto Jovem
15.
Am J Hum Genet ; 100(4): 650-658, 2017 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-28343630

RESUMO

Intellectual disability (ID) is a highly heterogeneous disorder involving at least 600 genes, yet a genetic diagnosis remains elusive in ∼35%-40% of individuals with moderate to severe ID. Recent meta-analyses statistically analyzing de novo mutations in >7,000 individuals with neurodevelopmental disorders highlighted mutations in PPM1D as a possible cause of ID. PPM1D is a type 2C phosphatase that functions as a negative regulator of cellular stress-response pathways by mediating a feedback loop of p38-p53 signaling, thereby contributing to growth inhibition and suppression of stress-induced apoptosis. We identified 14 individuals with mild to severe ID and/or developmental delay and de novo truncating PPM1D mutations. Additionally, deep phenotyping revealed overlapping behavioral problems (ASD, ADHD, and anxiety disorders), hypotonia, broad-based gait, facial dysmorphisms, and periods of fever and vomiting. PPM1D is expressed during fetal brain development and in the adult brain. All mutations were located in the last or penultimate exon, suggesting escape from nonsense-mediated mRNA decay. Both PPM1D expression analysis and cDNA sequencing in EBV LCLs of individuals support the presence of a stable truncated transcript, consistent with this hypothesis. Exposure of cells derived from individuals with PPM1D truncating mutations to ionizing radiation resulted in normal p53 activation, suggesting that p53 signaling is unaffected. However, a cell-growth disadvantage was observed, suggesting a possible effect on the stress-response pathway. Thus, we show that de novo truncating PPM1D mutations in the last and penultimate exons cause syndromic ID, which provides additional insight into the role of cell-cycle checkpoint genes in neurodevelopmental disorders.


Assuntos
Éxons , Deficiência Intelectual/genética , Mutação , Proteína Fosfatase 2C/genética , Adolescente , Ciclo Celular , Criança , Pré-Escolar , Humanos , Deficiência Intelectual/patologia , Adulto Jovem
16.
Pediatrics ; 139(2)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28096516

RESUMO

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.


Assuntos
Testes Genéticos , Triagem Neonatal , Saúde Pública , Análise de Sequência de DNA , Exoma/genética , Triagem de Portadores Genéticos , Pesquisa em Genética , Estudo de Associação Genômica Ampla , Variação Estrutural do Genoma/genética , Humanos , Recém-Nascido , Unidades de Terapia Intensiva Neonatal , Valor Preditivo dos Testes , Estudos Prospectivos , Estados Unidos
17.
Oncotarget ; 7(48): 79101-79116, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27738329

RESUMO

Abnormal activation of the epidermal growth factor receptor (EGFR) due to a deletion of exons 2-7 of EGFR (EGFRvIII) is a common alteration in glioblastoma (GBM). While this alteration can drive gliomagenesis, tumors harboring EGFRvIII are heterogeneous. To investigate the role for EGFRvIII activation in tumor phenotype we used a neural progenitor cell-based murine model of GBM driven by EGFR signaling and generated tumor progenitor cells with high and low EGFRvIII activation, pEGFRHi and pEGFRLo. In vivo, ex vivo, and in vitro studies suggested a direct association between EGFRvIII activity and increased tumor cell proliferation, decreased tumor cell adhesion to the extracellular matrix, and altered progenitor cell phenotype. Time-lapse confocal imaging of tumor cells in brain slice cultures demonstrated blood vessel co-option by tumor cells and highlighted differences in invasive pattern. Inhibition of EGFR signaling in pEGFRHi promoted cell differentiation and increased cell-matrix adhesion. Conversely, increased EGFRvIII activation in pEGFRLo reduced cell-matrix adhesion. Our study using a murine model for GBM driven by a single genetic driver, suggests differences in EGFR activation contribute to tumor heterogeneity and aggressiveness.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Receptores ErbB/genética , Receptores ErbB/metabolismo , Glioblastoma/diagnóstico por imagem , Deleção de Sequência , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ativação Enzimática , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Camundongos , Microscopia Confocal , Transplante de Neoplasias , Fosforilação , Imagem com Lapso de Tempo
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