Most Common Autosomal Dominant Disorders in Clinical Practice, a Review
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Marfan Syndrome
Marfan syndrome Description Marfan syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, blood vessels, and heart valves. The signs and symptoms of Marfan syndrome vary widely in severity, timing of onset, and rate of progression. Because connective tissue is found throughout the body, Marfan syndrome can affect many systems, often causing abnormalities in the heart, blood vessels, eyes, bones, and joints. The two primary features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and defects in the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening. Many people with Marfan syndrome have additional heart problems including a leak in the valve that connects two of the four chambers of the heart (mitral valve prolapse) or the valve that regulates blood flow from the heart into the aorta (aortic valve regurgitation). Leaks in these valves can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations). Individuals with Marfan syndrome are usually tall and slender, have elongated fingers and toes (arachnodactyly), loose joints, and have an arm span that exceeds their body height. -
Mutation in Genes FBN1, AKT1, and LMNA: Marfan Syndrome, Proteus Syndrome, and Progeria Share Common Systemic Involvement
Review Mutation in Genes FBN1, AKT1, and LMNA: Marfan Syndrome, Proteus Syndrome, and Progeria Share Common Systemic Involvement Tonmoy Biswas.1 Abstract Genetic mutations are becoming more deleterious day by day. Mutations of Genes named FBN1, AKT1, LMNA result specific protein malfunction that in turn commonly cause Marfan syndrome, Proteus syndrome, and Progeria, respectively. Articles about these conditions have been reviewed in PubMed and Google scholar with a view to finding relevant clinical features. Precise keywords have been used in search for systemic involvement of FBN1, AKT1, and LMNA gene mutations. It has been found that Marfan syndrome, Proteus syndrome, and Progeria commonly affected musculo-skeletal system, cardiovascular system, eye, and nervous system. Not only all of them shared identical systemic involvement, but also caused several very specific anomalies in various parts of the body. In spite of having some individual signs and symptoms, the mutual manifestations were worth mentio- ning. Moreover, all the features of the mutations of all three responsible genes had been co-related and systemically mentioned in this review. There can be some mutual properties of the genes FBN1, AKT1, and LMNA or in their corresponding proteins that result in the same presentations. This study may progress vision of knowledge regarding risk factors, patho-physiology, and management of these conditions, and relation to other mutations. Keywords: Genetic mutation; Marfan syndrome; Proteus syndrome; Progeria; Gene FBN1; Gene AKT1; Gene LMNA; Musculo-skeletal system; Cardiovascular system; Eye; Nervous system (Source: MeSH, NLM). Introduction Records in human mutation databases are increasing day by 5 About the author: Tonmoy The haploid human genome consists of 3 billion nucleotides day. -
Genetic Determinants Underlying Rare Diseases Identified Using Next-Generation Sequencing Technologies
Western University Scholarship@Western Electronic Thesis and Dissertation Repository 8-2-2018 1:30 PM Genetic determinants underlying rare diseases identified using next-generation sequencing technologies Rosettia Ho The University of Western Ontario Supervisor Hegele, Robert A. The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Rosettia Ho 2018 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Medical Genetics Commons Recommended Citation Ho, Rosettia, "Genetic determinants underlying rare diseases identified using next-generation sequencing technologies" (2018). Electronic Thesis and Dissertation Repository. 5497. https://ir.lib.uwo.ca/etd/5497 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Rare disorders affect less than one in 2000 individuals, placing a huge burden on individuals, families and the health care system. Gene discovery is the starting point in understanding the molecular mechanisms underlying these diseases. The advent of next- generation sequencing has accelerated discovery of disease-causing genetic variants and is showing numerous benefits for research and medicine. I describe the application of next-generation sequencing, namely LipidSeq™ ‒ a targeted resequencing panel for the identification of dyslipidemia-associated variants ‒ and whole-exome sequencing, to identify genetic determinants of several rare diseases. Utilization of next-generation sequencing plus associated bioinformatics led to the discovery of disease-associated variants for 71 patients with lipodystrophy, two with early-onset obesity, and families with brachydactyly, cerebral atrophy, microcephaly-ichthyosis, and widow’s peak syndrome. -
Repercussions of Inborn Errors of Immunity on Growth☆ Jornal De Pediatria, Vol
Jornal de Pediatria ISSN: 0021-7557 ISSN: 1678-4782 Sociedade Brasileira de Pediatria Goudouris, Ekaterini Simões; Segundo, Gesmar Rodrigues Silva; Poli, Cecilia Repercussions of inborn errors of immunity on growth☆ Jornal de Pediatria, vol. 95, no. 1, Suppl., 2019, pp. S49-S58 Sociedade Brasileira de Pediatria DOI: https://doi.org/10.1016/j.jped.2018.11.006 Available in: https://www.redalyc.org/articulo.oa?id=399759353007 How to cite Complete issue Scientific Information System Redalyc More information about this article Network of Scientific Journals from Latin America and the Caribbean, Spain and Journal's webpage in redalyc.org Portugal Project academic non-profit, developed under the open access initiative J Pediatr (Rio J). 2019;95(S1):S49---S58 www.jped.com.br REVIEW ARTICLE ଝ Repercussions of inborn errors of immunity on growth a,b,∗ c,d e Ekaterini Simões Goudouris , Gesmar Rodrigues Silva Segundo , Cecilia Poli a Universidade Federal do Rio de Janeiro (UFRJ), Faculdade de Medicina, Departamento de Pediatria, Rio de Janeiro, RJ, Brazil b Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Puericultura e Pediatria Martagão Gesteira (IPPMG), Curso de Especializac¸ão em Alergia e Imunologia Clínica, Rio de Janeiro, RJ, Brazil c Universidade Federal de Uberlândia (UFU), Faculdade de Medicina, Departamento de Pediatria, Uberlândia, MG, Brazil d Universidade Federal de Uberlândia (UFU), Hospital das Clínicas, Programa de Residência Médica em Alergia e Imunologia Pediátrica, Uberlândia, MG, Brazil e Universidad del Desarrollo, -
Orthopedic-Conditions-Treated.Pdf
Orthopedic and Orthopedic Surgery Conditions Treated Accessory navicular bone Achondroplasia ACL injury Acromioclavicular (AC) joint Acromioclavicular (AC) joint Adamantinoma arthritis sprain Aneurysmal bone cyst Angiosarcoma Ankle arthritis Apophysitis Arthrogryposis Aseptic necrosis Askin tumor Avascular necrosis Benign bone tumor Biceps tear Biceps tendinitis Blount’s disease Bone cancer Bone metastasis Bowlegged deformity Brachial plexus injury Brittle bone disease Broken ankle/broken foot Broken arm Broken collarbone Broken leg Broken wrist/broken hand Bunions Carpal tunnel syndrome Cavovarus foot deformity Cavus foot Cerebral palsy Cervical myelopathy Cervical radiculopathy Charcot-Marie-Tooth disease Chondrosarcoma Chordoma Chronic regional multifocal osteomyelitis Clubfoot Congenital hand deformities Congenital myasthenic syndromes Congenital pseudoarthrosis Contractures Desmoid tumors Discoid meniscus Dislocated elbow Dislocated shoulder Dislocation Dislocation – hip Dislocation – knee Dupuytren's contracture Early-onset scoliosis Ehlers-Danlos syndrome Elbow fracture Elbow impingement Elbow instability Elbow loose body Eosinophilic granuloma Epiphyseal dysplasia Ewing sarcoma Extra finger/toes Failed total hip replacement Failed total knee replacement Femoral nonunion Fibrosarcoma Fibrous dysplasia Fibular hemimelia Flatfeet Foot deformities Foot injuries Ganglion cyst Genu valgum Genu varum Giant cell tumor Golfer's elbow Gorham’s disease Growth plate arrest Growth plate fractures Hammertoe and mallet toe Heel cord contracture -
Craniosynostosis Genetics: the Mystery Unfolds
Review Article Craniosynostosis genetics: The mystery unfolds Inusha Panigrahi Department of Pediatrics, Genetic and Metabolic Unit, Advanced Pediatric Center, PGIMER, Chandigarh, India The syndromes associated with craniosynostosis Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis include Apert syndrome, Crouzon syndrome, Greig is common form of isolated craniosynostosis. The cephalopolysyndactyly, and Saethre-Chotzen syndrome. sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. It is genetically heterogeneous disorder with mutation Crouzon syndrome is one of the most common of the identifi ed in several genes, predominantly the fi broblast craniosynostosis syndromes. Apert syndrome accounts for growth factor receptor genes.[3,4] Saethre-Chotzen 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis syndrome and craniosynostosis (Boston-type) arise require multidisciplinary management. The following review from mutations in the Twist and muscle segment provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis homeobox 2 (MSX2) transcription factors, respectively. and genetic counseling. Rates of neuropsychological defi cits range from 35 to Key words: Apert syndrome, FGFR2 mutations, 50% in school-aged children with isolated single suture hydrocephalus, plagiocephaly, sutural synostosis, craniosynostosis.[5] Secondary effects of craniosynostosis syndromes may include vision problems and increased intracranial pressure, among others. Patients with TWIST gene Introduction mutations may have more ophthalmic abnormalities, including more strabismus, ptosis, and amblyopia.[6] The following discussion gives a comprehensive review Craniosynostosis, premature suture fusion, is one of of different disorders presenting with craniosynostosis, the most common craniofacial anomalies with incidence their diagnosis, and genetic counseling. -
Blueprint Genetics Craniosynostosis Panel
Craniosynostosis Panel Test code: MA2901 Is a 38 gene panel that includes assessment of non-coding variants. Is ideal for patients with craniosynostosis. About Craniosynostosis Craniosynostosis is defined as the premature fusion of one or more cranial sutures leading to secondary distortion of skull shape. It may result from a primary defect of ossification (primary craniosynostosis) or, more commonly, from a failure of brain growth (secondary craniosynostosis). Premature closure of the sutures (fibrous joints) causes the pressure inside of the head to increase and the skull or facial bones to change from a normal, symmetrical appearance resulting in skull deformities with a variable presentation. Craniosynostosis may occur in an isolated setting or as part of a syndrome with a variety of inheritance patterns and reccurrence risks. Craniosynostosis occurs in 1/2,200 live births. Availability 4 weeks Gene Set Description Genes in the Craniosynostosis Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ALPL Odontohypophosphatasia, Hypophosphatasia perinatal lethal, AD/AR 78 291 infantile, juvenile and adult forms ALX3 Frontonasal dysplasia type 1 AR 8 8 ALX4 Frontonasal dysplasia type 2, Parietal foramina AD/AR 15 24 BMP4 Microphthalmia, syndromic, Orofacial cleft AD 8 39 CDC45 Meier-Gorlin syndrome 7 AR 10 19 EDNRB Hirschsprung disease, ABCD syndrome, Waardenburg syndrome AD/AR 12 66 EFNB1 Craniofrontonasal dysplasia XL 28 116 ERF Craniosynostosis 4 AD 17 16 ESCO2 SC phocomelia syndrome, Roberts syndrome -
A Curated Gene List for Reporting Results of Newborn Genomic Sequencing
© American College of Medical Genetics and Genomics ORIGINAL RESEARCH ARTICLE A curated gene list for reporting results of newborn genomic sequencing Ozge Ceyhan-Birsoy, PhD1,2,3, Kalotina Machini, PhD1,2,3, Matthew S. Lebo, PhD1,2,3, Tim W. Yu, MD3,4,5, Pankaj B. Agrawal, MD, MMSC3,4,6, Richard B. Parad, MD, MPH3,7, Ingrid A. Holm, MD, MPH3,4, Amy McGuire, PhD8, Robert C. Green, MD, MPH3,9,10, Alan H. Beggs, PhD3,4, Heidi L. Rehm, PhD1,2,3,10; for the BabySeq Project Purpose: Genomic sequencing (GS) for newborns may enable detec- of newborn GS (nGS), and used our curated list for the first 15 new- tion of conditions for which early knowledge can improve health out- borns sequenced in this project. comes. One of the major challenges hindering its broader application Results: Here, we present our curated list for 1,514 gene–disease is the time it takes to assess the clinical relevance of detected variants associations. Overall, 954 genes met our criteria for return in nGS. and the genes they impact so that disease risk is reported appropri- This reference list eliminated manual assessment for 41% of rare vari- ately. ants identified in 15 newborns. Methods: To facilitate rapid interpretation of GS results in new- Conclusion: Our list provides a resource that can assist in guiding borns, we curated a catalog of genes with putative pediatric relevance the interpretive scope of clinical GS for newborns and potentially for their validity based on the ClinGen clinical validity classification other populations. framework criteria, age of onset, penetrance, and mode of inheri- tance through systematic evaluation of published evidence. -
Genetic Disorder
Genetic disorder Single gene disorder Prevalence of some single gene disorders[citation needed] A single gene disorder is the result of a single mutated gene. Disorder Prevalence (approximate) There are estimated to be over 4000 human diseases caused Autosomal dominant by single gene defects. Single gene disorders can be passed Familial hypercholesterolemia 1 in 500 on to subsequent generations in several ways. Genomic Polycystic kidney disease 1 in 1250 imprinting and uniparental disomy, however, may affect Hereditary spherocytosis 1 in 5,000 inheritance patterns. The divisions between recessive [2] Marfan syndrome 1 in 4,000 and dominant types are not "hard and fast" although the [3] Huntington disease 1 in 15,000 divisions between autosomal and X-linked types are (since Autosomal recessive the latter types are distinguished purely based on 1 in 625 the chromosomal location of Sickle cell anemia the gene). For example, (African Americans) achondroplasia is typically 1 in 2,000 considered a dominant Cystic fibrosis disorder, but children with two (Caucasians) genes for achondroplasia have a severe skeletal disorder that 1 in 3,000 Tay-Sachs disease achondroplasics could be (American Jews) viewed as carriers of. Sickle- cell anemia is also considered a Phenylketonuria 1 in 12,000 recessive condition, but heterozygous carriers have Mucopolysaccharidoses 1 in 25,000 increased immunity to malaria in early childhood, which could Glycogen storage diseases 1 in 50,000 be described as a related [citation needed] dominant condition. Galactosemia -
Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson-Gilford Progeria Syndrome
bioRxiv preprint doi: https://doi.org/10.1101/790477; this version posted October 2, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Paradoxical Aortic Stiffening and Subsequent Cardiac Dysfunction in Hutchinson‐Gilford Progeria Syndrome S‐I. Murtada1, Y. Kawamura1, A.W. Caulk1, H. Amadzadeh1, N. Mikush2, K. Zimmerman3, D. Kavanagh3, D. Weiss1, M. Latorre1, Z.W. Zhang4, G.S. Shadel5, D.T. Braddock3, J.D. Humphrey1,6 1Department of Biomedical Engineering Yale University, New Haven, CT, USA 2Translational Research Imaging Center, 3Department of Pathology, 4Section of Cardiovascular Medicine, and 6Vascular Biology and Therapeutics Program Yale School of Medicine, New Haven, CT, USA 5Molecular and Cellular Biology Salk Institute for Biological Studies, La Jolla, CA, USA Address for Correspondence: J.D. Humphrey, Ph.D. Department of Biomedical Engineering Yale University, New Haven, CT 06520 USA +1‐203‐432‐6428 [email protected] Running Title: Aortic Stiffening in late‐stage Progeria Keywords: progeria, aortic stiffness, pulse wave velocity, diastolic dysfunction, allometric scaling, aging 1 bioRxiv preprint doi: https://doi.org/10.1101/790477; this version posted October 2, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SUMMARY Hutchinson‐Gilford Progeria Syndrome (HGPS) is an ultra‐rare disorder with devastating sequelae resulting in early death, presently believed to stem primarily from heart failure secondary to central arterial stiffening. We analyze novel longitudinal cardiovascular data from a mouse model of HGPS (LmnaG609G/G609G) using allometric scaling and advanced computational modelling and show that a late‐stage increase in pulse wave velocity, with associated diastolic dysfunction but preserved systolic function, emerges with a loss of aortic function, independent of sex. -
Cardiomyopathy in Patients with Marfan Syndrome and Marfanoid Habitus
ORIGINAL ARTICLE Cardiomyopathy in patients with Marfan syndrome and marfanoid habitus Ekaterina Luneva MD, PhD1, Eduard Malev MD, PhD1,2, Alexandra Korshunova MD1,2, Svetlana Reeva MD PhD1,2, Eugeniy Timofeev MD PhD1,2 and Eduard Zemtsovsky Prof MD PhD1,2 Lunev E, Malev E, Korshunova A, et al. Cardiomyopathy in patients with worsening was detected in MS group comparing to control group. In marfanoid Marfan syndrome and marfanoid habitus. Curr Res Cardiol 2017;4(1): 9-13. habitus subjects, we found significant decrease of the circumferential strain in the interventricular septum and inferior wall. transforming growth factor-β1 OBJECTIVES: The term “Marfan cardiomyopathy” is used to indicate and -β2 serum levels were elevated in patients with Marfan syndrome. changes in left ventricular function in the absence of significant valvular Elevation of transforming growth factor-β1 was statistically nonsignificant pathology in Marfan syndrome. It is still unknown if there are any changes in unlike to transforming growth factor-β2 in the marfanoid habitus group. cardiac function in patients with similar connective tissue abnormality such Negative correlations between the serum level of transforming growth as marfanoid habitus. factor-β2 and systolic radial strain in the marfanoid habitus group also have been found. METHODS: In the study were included 98 persons - 8 patients with Marfan syndrome, 24 with marfanoid habitus and 66 healthy subjects. CONCLUSION: Worsening of regional myocardial deformation may be Echocardiography was performed to all patients. Speckle tracking the first sign of deterioration of the left ventricular systolic function and the echocardiography was used to assess the left ventricular deformation indices. -
Original Articles Evidence for Digenic Inheritance in Some Cases of Antley
26 J Med Genet 2000;37:26–32 Original articles J Med Genet: first published as 10.1136/jmg.37.1.26 on 1 January 2000. Downloaded from Department of Clinical Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK Evidence for digenic inheritance in some cases of W Reardon M Baraitser Antley-Bixler syndrome? R M Winter Molecular Genetics Unit, Institute of Child Health, London, UK William Reardon, Anne Smith, John W Honour, Peter Hindmarsh, Debipriya Das, A Smith Gill Rumsby, Isabelle Nelson, Sue Malcolm, Lesley Adès, David Sillence, I Nelson Dhavendra Kumar, Celia DeLozier-Blanchet, Shane McKee, Thaddeus Kelly, S Malcolm Wallace L McKeehan, Michael Baraitser, Robin M Winter Department of Chemical Pathology, University College London Hospitals, London, UK J W Honour Abstract The Antley-Bixler syndrome represents the D Das The Antley-Bixler syndrome has been severe end of the spectrum of syndromic G Rumsby thought to be caused by an autosomal craniosynostosis. Many such patients have London Centre for recessive gene. However, patients with this choanal atresia and severe respiratory distress, Paediatric often resulting in early death. In contrast with Endocrinology, phenotype have been reported with a new University College dominant mutation at the FGFR2 locus as most clinically similar forms of syndromic Hospital, London, UK well as in the oVspring of mothers taking craniosynostosis, which are transmitted in an P Hindmarsh the antifungal agent fluconazole during autosomal dominant manner, Antley-Bixler Departments of early pregnancy. In addition to the cranio- syndrome has been thought to be an autosomal Clinical Genetics and recessive disorder.7 This is based upon three Paediatrics and Child synostosis and joint ankylosis which are the 8–10 Health, New Children’s clinical hallmarks of the condition, many reports of aVected sibs and the birth of Hospital, Parramatta, patients, especially females, have genital aVected subjects to consanguineous par- NSW 2124, Australia ents.91112It should be noted that joint ankylo- abnormalities.