ORCID Profile
0000-0003-1586-0890
Current Organisations
National Institutes of Health
,
Hummingbird House, Paediatric Hospice
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Publisher: Wiley
Date: 25-04-2018
DOI: 10.1002/AJMG.A.38717
Publisher: Elsevier BV
Date: 2019
Publisher: Cold Spring Harbor Laboratory
Date: 04-09-2018
DOI: 10.1101/408492
Abstract: RNA sequencing (RNA-seq) is a complementary approach for Mendelian disease diagnosis for patients in whom exome-sequencing is not informative. For both rare neuromuscular and mitochondrial disorders, its application has improved diagnostic rates. However, the generalizability of this approach to erse Mendelian diseases has yet to be evaluated. We sequenced whole blood RNA from 56 cases with undiagnosed rare diseases spanning 11 erse disease categories to evaluate the general application of RNA-seq to Mendelian disease diagnosis. We developed a robust approach to compare rare disease cases to existing large sets of RNA-seq controls (N=1,594 external and N=31 family-based controls) and demonstrated the substantial impacts of gene and variant filtering strategies on disease gene identification when combined with RNA-seq. Across our cohort, we observed that RNA-seq yields a 8.5% diagnostic rate. These diagnoses included diseases where blood would not intuitively reflect evidence of disease. We identified RARS2 as an under-expression outlier containing compound heterozygous pathogenic variants for an in idual exhibiting profound global developmental delay, seizures, microcephaly, hypotonia, and progressive scoliosis. We also identified a new splicing junction in KCTD7 for an in idual with global developmental delay, loss of milestones, tremors and seizures. Our study provides a broad evaluation of blood RNA-seq for the diagnosis of rare disease.
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.YMGME.2021.07.013
Abstract: Neurobeachin (NBEA) was initially identified as a candidate gene for autism. Recently, variants in NBEA have been associated with neurodevelopmental delay and childhood epilepsy. Here, we report on a novel NBEA missense variant (c.5899G > A, p.Gly1967Arg) in the Domain of Unknown Function 1088 (DUF1088) identified in a child enrolled in the Undiagnosed Diseases Network (UDN), who presented with neurodevelopmental delay and seizures. Modeling of this variant in the Caenorhabditis elegans NBEA ortholog, sel-2, indicated that the variant was damaging to in vivo function as evidenced by altered cell fate determination and trafficking of potassium channels in neurons. The variant effect was indistinguishable from that of the reference null mutation suggesting that the variant is a strong hypomorph or a complete loss-of-function. Our experimental data provide strong support for the molecular diagnosis and pathogenicity of the NBEA p.Gly1967Arg variant and the importance of the DUF1088 for NBEA function.
Publisher: SAGE Publications
Date: 08-06-2018
Abstract: Leukodystrophies and genetic leukoencephalopathies are a heterogeneous group of heritable disorders that affect the glial-axonal unit. As more patients with unsolved leukodystrophies and genetic leukoencephalopathies undergo next generation sequencing, causative mutations in genes leading to central hypomyelination are being identified. Two such in iduals presented with arthrogryposis multiplex congenita, congenital hypomyelinating neuropathy, and central hypomyelination with early respiratory failure. Whole exome sequencing identified biallelic mutations in the CNTNAP1 gene: homozygous c.1163G C (p.Arg388Pro) and compound heterozygous c.967T C (p.Cys323Arg) and c.319C T (p.Arg107*). Sural nerve and quadriceps muscle biopsies demonstrated progressive, severe onion bulb and axonal pathology. By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier. Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients. These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita.
Publisher: Springer Science and Business Media LLC
Date: 06-2019
Publisher: Wiley
Date: 23-10-2017
DOI: 10.1111/CTS.12512
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2014
Publisher: Wiley
Date: 07-05-2021
DOI: 10.1002/MGG3.1692
Abstract: Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma‐pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh‐like syndromes. Here, we describe a case of a 9‐year‐old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA , a known pathogenic variant (c.91C T (p.R31*)), and a variant of unknown significance (c.454G A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder. We, therefore, consider whether c.454G A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.
Publisher: Elsevier BV
Date: 06-2017
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 2019
Publisher: Cold Spring Harbor Laboratory
Date: 21-03-2018
DOI: 10.1101/286146
Abstract: Brain malformations are caused by 17p13.3 deletions: lissencephaly with deletions of the larger Miller-Dieker syndrome region or smaller deletions of only PAFAH1B1 , as well as various abnormalities, including white matter changes, in the distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE / CRK and PAFAH1B1 loci. We analyzed the clinical features of five in iduals from four families with 17p13.3 deletions between and not including YWHAE / CRK and PAFAH1B1 identified among in iduals undergoing clinical chromosomal microarray testing. Four in iduals from three families have multi-focal white matter lesions and hypermobile joints, while a fifth had a normal MRI. A combination of our patients and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ∼345 kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this. While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE , our cohort contributes evidence to the presence of additional genes within 17p13.3 required for proper brain development.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-04-2019
DOI: 10.1212/NXI.0000000000000560
Abstract: To highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL). Retrospective chart review. Patients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL. Early and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome. This study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.
Publisher: Wiley
Date: 09-05-2016
DOI: 10.1002/ANA.24650
Publisher: Elsevier BV
Date: 08-2018
Publisher: Elsevier BV
Date: 10-2016
Publisher: Elsevier BV
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 15-11-2018
DOI: 10.1038/S41582-018-0077-9
Abstract: In the original version of this Review published online and in print, the contribution of attendees of the International Neuroimmune Meeting to the content of the Review was not acknowledged. The author list has been corrected in the PDF and HTML versions of this article to acknowledge that the Review was written on behalf of attendees of the International Neuroimmune Meeting, and the names of the attendees have been added to the HTML version.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2021
DOI: 10.1038/S41597-021-00894-Y
Abstract: Every year in iduals experience symptoms that remain undiagnosed by healthcare providers. In the United States, these rare diseases are defined as a condition that affects fewer than 200,000 in iduals. However, there are an estimated 7000 rare diseases, and there are an estimated 25–30 million Americans in total (7.6–9.2% of the population as of 2018) affected by such disorders. The NIH Common Fund Undiagnosed Diseases Network (UDN) seeks to provide diagnoses for in iduals with undiagnosed disease. Mass spectrometry-based metabolomics and lipidomics analyses could advance the collective understanding of in idual symptoms and advance diagnoses for in iduals with heretofore undiagnosed disease. Here, we report the mass spectrometry-based metabolomics and lipidomics analyses of blood plasma, urine, and cerebrospinal fluid from 148 patients within the UDN and their families, as well as from a reference population of over 100 in iduals with no known metabolic diseases. The raw and processed data are available to the research community so that they might be useful in the diagnoses of current or future patients suffering from undiagnosed disorders.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1038/GIM.2017.128
Publisher: Elsevier BV
Date: 02-0011
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
Publisher: Hindawi Limited
Date: 27-08-2015
DOI: 10.1002/HUMU.22840
Publisher: Oxford University Press (OUP)
Date: 31-08-2017
DOI: 10.1534/GENETICS.117.203067
Abstract: Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.
Publisher: American Society of Hematology
Date: 13-02-2019
DOI: 10.1182/BLOODADVANCES.2018027417
Abstract: Familial HLH can present as chronic isolated neuroinflammation. CNS-isolated HLH responds to hematopoietic cell transplantation.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Wiley
Date: 16-04-2019
DOI: 10.1002/MGG3.686
Publisher: Elsevier BV
Date: 03-2019
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.YMGME.2014.12.433
Abstract: Leukodystrophies are inherited disorders whose primary pathophysiology consists of abnormal deposition or progressive disruption of brain myelin. Leukodystrophy patients manifest many of the same symptoms and medical complications despite the wide spectrum of genetic origins. Although no definitive cures exist, all of these conditions are treatable. This report provides the first expert consensus on the recognition and treatment of medical and psychosocial complications associated with leukodystrophies. We include a discussion of serious and potentially preventable medical complications and propose several preventive care strategies. We also outline the need for future research to prioritize clinical needs and subsequently develop, validate, and optimize specific care strategies.
Publisher: Wiley
Date: 28-03-2019
DOI: 10.1002/AJMG.A.61134
No related grants have been discovered for Jennifer Louise Patrick Murphy.