435 research outputs found
Pathogenic Variants in Fucokinase Cause a Congenital Disorder of Glycosylation
FUK encodes fucokinase, the only enzyme capable of converting L-fucose to fucose-1-phosphate, which will ultimately be used for synthesizing GDP-fucose, the donor substrate for all fucosyltransferases. Although it is essential for fucose salvage, this pathway is thought to make only a minor contribution to the total amount of GDP-fucose. A second pathway, the major de novo pathway, involves conversion of GDP-mannose to GDP-fucose. Here we describe two unrelated individuals who have pathogenic variants in FUK and who presented with severe developmental delays, encephalopathy, intractable seizures, and hypotonia. The first individual was compound heterozygous for c.667T>C (p.Ser223Pro) and c.2047C>T (p.Arg683Cys), and the second individual was homozygous for c.2980A>C (p.Lys994Gln). Skin fibroblasts from the first individual confirmed the variants as loss of function and showed significant decreases in total GDP-[3H] fucose and [3H] fucose-1-phosphate. There was also a decrease in the incorporation of [5,6-3H]-fucose into fucosylated glycoproteins. Lys994 has previously been shown to be an important site for ubiquitin conjugation. Here, we show that loss-of-function variants in FUK cause a congenital glycosylation disorder characterized by a defective fucose-salvage pathway
Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders
Familias de genes; Trastornos del desarrollo neurolĂłgico; HnRNPsFamĂlies genètiques; Trastorns del desenvolupament neurològic; HnRNPsGene families; Neurodevelopmental disorders; HnRNPsBackground
With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.
Methods
We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.
Results
We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.
Conclusions
Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.This work was supported, in part, by the U.S. National Institutes of Health (R01MH101221) to E.E.E. Research reported in this publication was supported, in part, by the National Institute of Neurological Disorders and Stroke (NINDS) under award number K08NS092898, Jordan’s Guardian Angels, and the Brotman Baty Institute (to G.M.M.). M.I., A.C., and A.S. were supported by the G.E.N.E. (Genomic analysis Evaluation Network) Research Project founded by Progetti di Innovazione in Ambito Sanitario e Socio Sanitario (Bando EX decreto n.2713 28.02.2018) Regione Lombardia. D. L was supported by the German Research Foundation (DFG; LE 4223/1). B.B.A.d.V. and L.E.L.M.V. were supported by grants from the Dutch Organization for Health Research and Development (ZON-MW grants 917–86–319 and 912–12–109). M.E., O.G., and C.R. received funding from the Italian Ministry of Health (Project RC n. 2757328). I.T. is supported by generous donors to the Children’s Mercy Research Institute and the Genomic Answers for Kids program. K.X. is supported by the National Natural Science Foundation of China (NSFC: 8173000779) and the Science and Technology Major Project of Hunan Provincial Science and Technology Department (2018SK1030). M.A.G. was supported by the U.S. National Institutes of Health (T32HG000035). E.E.E. is an investigator of the Howard Hughes Medical Institute
Microdeletion of 6q16.1 encompassing EPHA7 in a child with mild neurological abnormalities and dysmorphic features: case report
<p>Abstract</p> <p>Background</p> <p>Of the fewer than 100 cases reported within the literature of constitutional deletions involving the long arm of chromosome 6, only five have been characterized using high-resolution microarray analysis. Reported 6q deletion patients show a high incidence of mental retardation, ear anomalies, hypotonia, and postnatal growth retardation.</p> <p>Results</p> <p>We report a 16-month-old male presenting with developmental delay and dysmorphic features who was found by array-based comparative genomic hybridization (aCGH) to have a ~2.16 Mb <it>de novo </it>deletion within chromosome band 6q16.1 that encompasses only two genes. Expression studies of the mouse homologue of one of the genes, the ephrin receptor 7 gene (<it>EPHA7</it>), have shown the gene functions during murine embryogenesis to form cortical domains, determine brain size and shape, and play a role in development of the central nervous system (CNS).</p> <p>Discussion</p> <p>Our results suggest that deletion of <it>EPHA7 </it>plays a role in the neurologic and dysmorphic features, including developmental delay, hypotonia, and ear malformations, observed in some 6q deletion patients.</p
How do women prepare for pregnancy? Preconception experiences of women attending antenatal services and views of health professionals
Copyright: © 2014 Stephenson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Main objective - To determine the extent to which women plan and prepare for pregnancy.
Methods - Cross-sectional questionnaire survey of pregnant women attending three maternity services in London about knowledge and uptake of preconception care; including a robust measure of pregnancy planning, and phone interviews with a range of health care professionals.
Main results - We recruited 1173/1288 (90%) women, median age of 32 years. 73% had clearly planned their pregnancy, 24% were ambivalent and only 3% of pregnancies were unplanned. 51% of all women and 63% of those with a planned pregnancy took folic acid before pregnancy. 21% of all women reported smoking and 61% reported drinking alcohol in the 3 months before pregnancy; 48% of smokers and 41% of drinkers reduced or stopped before pregnancy. The 51% of all women who reported advice from a health professional before becoming pregnant were more likely to adopt healthier behaviours before pregnancy [adjusted odds ratios for greatest health professional input compared with none were 2.34 (95% confidence interval 1.54–3.54) for taking folic acid and 2.18 (95% CI 1.42–3.36) for adopting a healthier diet before pregnancy]. Interviews with 20 health professionals indicated low awareness of preconception health issues, missed opportunities and confusion about responsibility for delivery of preconception care.
Significance of the findings - Despite a high level of pregnancy planning, awareness of preconception health among women and health professionals is low, and responsibility for providing preconception care is unclear. However, many women are motivated to adopt healthier behaviours in the preconception period, as indicated by halving of reported smoking rates in this study. The link between health professional input and healthy behaviour change before pregnancy is a new finding that should invigorate strategies to improve awareness and uptake of pre-pregnancy health care, and bring wider benefits for public health.Department of Healt
Symptom Clusters in Acute Myocardial Infarction: A Secondary Data Analysis
Background: Early recognition of acute myocardial infarction (AMI) symptoms and reduced time to treatment may reduce morbidity and mortality. People having AMI experience a constellation of symptoms, but the common constellations or clusters of symptoms have yet to be identified. Objectives: To identify clusters of symptoms that represent AMI. Methods: This was a secondary data analysis of nine descriptive, cross-sectional studies that included data from 1,073 people having AMI in the United States and England. Data were analyzed using latent class cluster analysis, an atheoretical method that uses only information contained in the data. Results: Five distinct clusters of symptoms were identified. Age, race, and sex were statistically significant in predicting cluster membership. None of the symptom clusters described in this analysis included all of the symptoms that are considered typical. In one cluster, subjects had only a moderate to low probability of experiencing any of the symptoms analyzed. Discussion: Symptoms of AMI occur in clusters, and these clusters vary among persons. None of the clusters identified in this study included all of the symptoms that are included typically as symptoms of AMI (chest discomfort, diaphoresis, shortness of breath, nausea, and lightheadedness). These AMI symptom clusters must be communicated clearly to the public in a way that will assist them in assessing their symptoms more efficiently and will guide their treatment-seeking behavior. Symptom clusters for AMI must also be communicated to the professional community in a way that will facilitate assessment and rapid intervention for AMI
Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes
Objective: To expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.
Methods: Whole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.
Results: Common clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that de- fective KARS function is responsible for the phenotypes in these individuals.
Conclusions: Our results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease
Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay
We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C. This gene has not previously been associated with a Mendelian disease, and based on the population database, gnomAD, the gene has a low tolerance for loss-of-function variants (pLI = 1, o/e = 0.07). We functionally evaluated the PPP5C variant in C. elegans by knocking the variant into the orthologous gene, pph-5, at the corresponding residue, Ala48Thr. We employed assays in three different biological processes where pph-5 was known to function through opposing the activity of genes, mec-15 and sep-1. We demonstrated that, in contrast to control animals, the pph-5 Ala48Thr variant suppresses the neurite growth phenotype and the GABA signaling defects of mec-15 mutants, and the embryonic lethality of sep-1 mutants. The Ala48Thr variant did not display dominance and behaved similarly to the reference pph-5 null, indicating that the variant is likely a strong hypomorph or complete loss-of-function. We conclude that pph-5 Ala48Thr is damaging in C. elegans. By extension in the proband, PPP5C p.Ala47Thr is likely damaging, the de novo dominant presentation is consistent with haplo-insufficiency, and the PPP5C variant is likely responsible for one or more of the proband\u27s phenotypes
Microdeletion of 6q16.1 encompassing EPHA7 in a child with mild neurological abnormalities and dysmorphic features: a case report
Abstract Background Of the fewer than 100 cases reported within the literature of constitutional deletions involving the long arm of chromosome 6, only five have been characterized using high-resolution microarray analysis. Reported 6q deletion patients show a high incidence of mental retardation, ear anomalies, hypotonia, and postnatal growth retardation. Results We report a 16-month-old male presenting with developmental delay and dysmorphic features who was found by array-based comparative genomic hybridization (aCGH) to have a ~2.16 Mb de novo deletion within chromosome band 6q16.1 that encompasses only two genes. Expression studies of the mouse homologue of one of the genes, the ephrin receptor 7 gene (EPHA7), have shown the gene functions during murine embryogenesis to form cortical domains, determine brain size and shape, and play a role in development of the central nervous system (CNS). Discussion Our results suggest that deletion of EPHA7 plays a role in the neurologic and dysmorphic features, including developmental delay, hypotonia, and ear malformations, observed in some 6q deletion patients
The Lantern Vol. 46, No. 2, April 1980
• The Voyage to Man\u27s Destiny • If I Could Keep the Times • Barstool Blues • I Didn\u27t Know • Felonious, Friend • Cool Ride • Georgia • Let Us Eat and Drink • In a Field • New Born Foal • Union to Freedom • In the Woods • Anthropomorphism • Runner • C.C. • Lake Attempt • A Fuzzy Blue Line • Trust Me • Haven\u27t We Met Before? • Rationality • Expecting Me • Short Storyhttps://digitalcommons.ursinus.edu/lantern/1116/thumbnail.jp
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