JBM  Vol.7 No.12 , December 2019
Genomic Analysis of 727 Patients with Ehlers-Danlos Syndrome I: Clinical Perspective Relates 23 Genes to a Maternally Influenced Arthritis-Adrenaline Disorder
Abstract: A novel medical approach for qualifying DNA variants found by whole exome sequencing (WES) facilitates discovery of new gene-disease relationships and emphasizes that DNA change must be correlated with clinical findings before having utility for diagnosis. Delineation of an arthritis-adrenaline disorder (AAD) process qualified variants in 23 genes as diagnostically useful in 727 patients having WES among 1656 with Ehlers-Danlos syndrome (EDS); these results distinguished them from 102 patients who had qualified gene variants among 728 with developmental disability. Excess maternal transmission of AAD by pedigree analysis plus 167 maternally versus 111 paternally transmitted DNA variants and 75 patients with only mitochondrial DNA variants suggest maternal influence on inheritance of AAD and its subsumed EDS types. Genes grouped by impact on different connective tissue elements showed variation in similar numbers of patients with hypermobile or classical EDS, benign joint hypermobility, or predominant dysautonomia: COL7A1, FLG acting on skin in 21 patients; SCN9A/10A/11A, POLG on nerve in 24; COL6A1/A2/A3, COL12 on muscle in 19; COL5A1/A2, FBN1, TGFB2/3, TGFBR1/2 on tissue matrix in 51; COL3A1, VWF on vessel in 18; COL1A1/A2, COL11A1/A2 acting on bone in 15 patients. Each gene group acts through a postulated articulo-autonomic dysplasia cycle to produce reciprocal tissue laxity and dysautonomia findings that transcend EDS types. This same tissue laxity-dysautonomia cycle acts to produce secondary complications in disorders ranging from distinctive connective tissue dysplasias to developmental disorders with hypotonia and acquired conditions with autonomic imbalance. Several altered genes were previously associated with neuromuscular disorders, foreshadowing a large myopathic EDS category that will incorporate many patients with hypermobility. The importance of muscle for joint constraint supports present exercise and future mesenchymal stem cell therapies, whether AAD is genetic or epigenetic from trauma, surgery, inflammation, or aging.
Cite this paper: Wilson, G. (2019) Genomic Analysis of 727 Patients with Ehlers-Danlos Syndrome I: Clinical Perspective Relates 23 Genes to a Maternally Influenced Arthritis-Adrenaline Disorder. Journal of Biosciences and Medicines, 7, 181-204. doi: 10.4236/jbm.2019.712015.

[1]   Franklin, B. (1952) Poor Richard’s Almanack (orig. 1732-1952). Peter Pauper Press Inc., Mount Vernon, 24.

[2]   Tinkle, B.T. and Levy, H.P. (2019) Symptomatic Joint Hypermobility: The Hypermobile Type of Ehlers-Danlos Syndrome and the Hypermobility Spectrum Disorders. Medical Clinics North America, 103, 1021-1033.

[3]   Malfait, F., Francomano, C., Byers, P., et al. (2017) The 2017 International Classification of the Ehlers-Danlos Syndromes. American Journal of Medical Genetics Part C Seminars in Medical Genetics, 175, 5-7.

[4]   Tinkle, B., Castori, M., Berglund, B., et al. (2017) Hypermobile Ehlers-Danlos Syndrome (a.k.a. Ehlers-Danlos Syndrome Type III and Ehlers-Danlos Syndrome Hypermobility Type): Clinical Description and Natural History. American Journal of Medical Genetics Part C Seminars in Medical Genetics 175, 48-69.

[5]   Simpson, M.R. (2006) Benign Joint Hypermobility Syndrome: Evaluation, Diagnosis, and Management. Journal of American Osteopathic Association, 106, 531-536.

[6]   Ehlers, E. (1901) Cutis laxa, Neigung zu ha Haemorrhagien in der Haut, Lokerung mehrerer Artikulationen. Dermatologie Z, 8, 173-174.

[7]   Danlos, H.A. (1908) Un cas de cutis laxa avec tumeurs pare contusion chronique des coudes et des genoux (xanthoma juvénile pseudo-diabétique de MM, Hallopeau et Macé de Lépinay). Bulletin Societé French Dermatologie Syphilis, 19, 70-72.

[8]   Bowen, J.M., Sobey, G.J., Burrows, N.P., et al. (2017) Ehlers-Danlos Syndrome, Classical Type. American Journal of Medical Genetics Part C Seminars in Medical Genetics, 175, 27-39.

[9]   Byers, P.H., Belmont, J., Black, J., et al. (2017) Diagnosis, Natural History, and Management in Vascular Ehlers-Danlos Syndrome. American Journal of Medical Genetics Part C Seminars in Medical Genetics, 175, 27-39.

[10]   McKusick, V.A. (1955) Heritable Disorders of Connective Tissue. I. The Clinical Behavior of Hereditary Syndromes. Journal of Chronic Disease, 2, 491-499.

[11]   Gazit, Y., Nahir, A.M., Grahame, R. and Jacob, G. (2003) Dysautonomia in the Joint Hypermobility Syndrome. American Journal of Medicine, 115, 33-40.

[12]   Lyons, J.J., Dietz, H.C., Sleeper, L.A., et al. (2016) Elevated Basal Serum Tryptase Identifies a Multisystem Disorder Associated with Increased TPSAB1 Copy Number. Nature Genetics, 48, 1564-1569.

[13]   Chey, W.D., Kurlander, J. and Eswaran, S. (2015) Irritable Bowel Syndrome: A Clinical Review. Journal of the American Medical Association, 313, 949-958.

[14]   Benarroch, E.E. (2012) Postural Tachycardia Syndrome: A Heterogeneous and Multifactorial Disorder. Mayo Clinic Proceedings, 87, 1214-1225.

[15]   Ravi, A., Butterfield, J. and Weiler, C.R. (2014) Mast Cell Activation Syndrome: Improved Identification by Combined Determinations of Serum Tryptase and 24-Hour Urine 11β-Prostaglandin2α. Journal of Allergy and Clinical Immunology Practice, 2, 775-778.

[16]   Theoharides, T.C., Valent, P. and Akin, C. (2015) Mast Cells, Mastocytosis, and Related Disorders. New England Journal of Medicine, 373, 163-172.

[17]   Wilson, G.N. (2019) Clinical Analysis Supports Articulo-Autonomic Dysplasia as a Unifying Pathogenic Mechanism in Ehlers-Danlos Syndrome and Related Conditions. The Journal of Bioscience and Medicine, 7, 149-168.

[18]   The term adrenaline is shorthand for the complex mixtures of catecholamines that mediate excess adrenocortical/adrenergic activity.

[19]   Clauw, D.J. (2014) Fibromyalgia: A Clinical Review. Journal of the American Medical Association, 311, 1547-1555.

[20]   Aronowitz, R.A. (2001) When Do Symptoms Become a Disease? Annals of Internal Medicine, 134, 803-808.

[21]   Norheim, K.B., Jonsson, G. and Omdal, R. (2011) Biological Mechanisms of Chronic Fatigue. Rheumatology, 50, 1009-1018.

[22]   McKusick Numbers.

[23]   Khavkin, J. and Ellis, D.A. (2011) Aging Skin: Histology, Physiology, and Pathology. Facial Plastic Surgery Clinics of North America, 19, 229-234.

[24]   Wyandt, H.E., Wilson, G.N. and Tonk, V.S. (2017) Gene and Genome Sequencing: Interpreting Genetic Variation at the Nucleotide Level. In: Human Chromosome Variation: Heteromorphism, Polymorphism, and Pathogenesis, 2nd Edition, Springer, Singapore, Ch. 11.

[25]   Bamshad, M.J., Ng, S.B., Bigham, A.W., et al. (2011) Exome Sequencing as a Tool for Mendelian Disease Gene Discovery. Nature Reviews Genetics, 12, 745-755.

[26]   Yang, Y., Muzny, D.M., Reid, J.G., et al. (2013) Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders. New England Journal of Medicine, 369, 1502-1511.

[27]   Fresard, L., Smail, C., Ferraro, N.M., et al. (2019) Identification of Rare-Disease Genes Using Blood Transcriptome Sequencing and Large Control Cohorts. Nature Medicine, 25, 911-919.

[28]   Wilson, G.N. (2014) Presymptomatic and Preimplantation Genetic Di-agnosis: Neurology, Next Genetics, and the Next Generation. Journal of the American Medical Association Neurology, 71, 403-404.

[29]   Weerakkody, R.A., Vandrovkova, J., Kanonidau, C., et al. (2016) Targeted Next-Generation Sequencing Makes New Molecular Diagnoses and Expands Genotype-Phenotype Relationship in Ehlers-Danlos Syndrome. Genetics in Medicine, 18, 1119-1127.

[30]   Hunter, D.J. and Drazen, J.M. (2019) Has the Genome Granted Our Wish Yet? New England Journal of Medicine, 380, 2391-2393.

[31]   Annas, G.J. and Elias, S. (2014) 23 and Me and the FDA. New England Journal of Medicine, 370, 2248-2249.

[32]   Retterer, K., Scuffins, J., Schmidt, D., et al. (2015) Assessing Copy Number from Exome Sequencing and Exome Array CGH Based on CNV Spectrum in a Large Clinical Cohort. Genetics in Medicine, 17, 623-629.

[33]   MacArthur, D.G., Manolio, T.A, Dimmick, D.P., et al. (2014) Guidelines for Investigating Causality of Sequence Variants in Human Disease. Nature, 508, 469-476.

[34]   Green, R.C., Berg, J.S., Grody, W.W., et al. (2013) American College of Medical Genetics and Genomics. ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing. Genetics in Medicine, 15, 565-574.

[35]   Richards, S., Aziz, N., Bale, S., et al. (2015) ACMG Laboratory Quality Assurance Committee. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation. Genetics in Medicine, 17, 405-424.

[36]   Campbell, I. (2007) Chi-Squared and Fisher-Irwin Tests of Two-by-Two Tables with Small Sample Recommendations. Statistics in Medicine, 26, 3661-3675.

[37]   Databases of DNA Variants Include Those in Ostensibly Normal People., Gnomad.
Lek, M., Karczewski, K.J., Minikel, E.V., et al. (2016) Analysis of Protein-Coding Genetic Variation in 60,706 Humans. Nature, 536, 285-291.

[38]   Posey, J.E., Harel, T., Liu, P., et al. (2017) Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. New England Journal of Medicine, 376, 21-31.

[39]   Grantham, R. (1974) Amino Acid Difference Formula to Help Explain Protein Evolution. Science, 185, 862-864.

[40]   Aydin, H., Tatar C., Savas, O.A., et al. (2018) The Effects of Local and Systemic Administration of Proline on Wound Healing in Rats. Journal of Investigative Surgery, 1, 1-7.

[41]   Colombi, M., Dordoni, C., Venturini, M., et al. (2017) Delineation of Ehlers-Danlos Syndrome Phenotype Due to the c.934C > T, p. (Arg312Cys) Mutation in COL1A1: Report on a Three-Generation Family without Cardiovascular Events, and Literature Review. American Journal of Medical Genetics Part A, 173, 524-530.

[42]   Lisman, T., Raynal, N., Groeneveld, D., et al. (2006) A Single High-Affinity Binding Site for von Willebrand Factor in Collagen III, Identified Using Synthetic Triple-Helical Peptides. Blood, 108, 3753-3756.

[43]   Whiffin, N., Ware, J.S. and O’Donnell-Luria, A. (2019) Improving the Understanding of Genetic Variants in Rare Disease with Large-Scale Reference Populations. Journal of the American Medical Association, 322, 1305-1306.

[44]   Han, C., Janneke, G.J., Hoeijmakers, S.L., et al. (2012) Functional Profiles of SCN9A Variants in Dorsal Root Ganglion Neurons and Superior Cervical Ganglion Neurons Correlate with Autonomic Symptoms in Small Fibre Neuropathy. Brain, 135, 2613-2628.

[45]   Rai, G., Rai, R., Saeidian, A.H. and Rai, M. (2016) Microarray to Deep Sequencing: Transcriptome and miRNA Profiling to Elucidate Molecular Pathways in Systemic Lupus Erythematosus. Immunology Research, 64, 14-24.

[46]   Lander, R.S. (2011) Initial Impact of the Sequencing of the Human Genome. Nature, 470, 187-197.

[47]   Pieczenik, S.R. and Neustadt, J. (2007) Mitochondrial Dysfunction and Molecular Pathways of Disease. Experimental and Molecular Pathology, 83, 84-92.

[48]   Liu, X., Wu, H., Byrne, M., Krane, S. and Jaenisch, R. (1997) Type III Collagen Is Crucial for Collagen I Fibrillogenesis and for Normal Cardiovascular Development. Proceeding of the National Academy of Sciences, 94, 1852-1856.

[49]   Serjeant, G.R. and Vichinsky, E. (2018) Variability of Homozygous Sickle Cell Disease: The Role of Alpha and Beta Globin Chain Variation and Other Factors. Blood Cells, Molecules and Diseases, 70, 66-77.

[50]   Scacheri, P.C., Gil-landers, E.M., Subramony, S.H., et al. (2002) Novel Mutations in Collagen VI Genes: Expansion of the Bethlem Myopathy Phenotype. Neurology, 58, 593-602.

[51]   Brady, A.F., Demirdas, S., Fournel-Gigleux, S., et al. (2017) The Ehlers-Danlos Syndromes, Rare Types. American Journal of Medical Genetics Part C Seminars in Medical Genetics, 175, 70-115.

[52]   Stern, C.M., Pepin, M.J., Stoler, J.M., et al. (2017) Musculoskeletal Conditions in a Pediatric Population with Ehlers-Danlos Syndrome. Journal of Pediatrics, 181, 261-266.

[53]   Hainstock, M.R., Gruchala, N.E., Fike, N., et al. (2008) Postural Orthostatic Tachycardia in a Teenager with Klinefelter Syndrome. Congenital Heart Disease, 3, 440-442.

[54]   Mitchell, T. and Barlow, C.E. (2011) Review of the Role of Exercise in Improving Quality of Life in Healthy Individuals and in Those with Chronic Diseases. Current Sports Medicine Reports, 10, 211-216.

[55]   Bathen, T., Hangman, A.B., Hoff, M., et al. (2013) Multi-disciplinary Treatment of Disability in Ehlers-Danlos Syndrome Hypermobility Type/Hypermobility Syndrome: A Pilot Study Using a Combination of Physical and Cognitive Behavioral Therapy on 12 Women. American Journal of Medical Genetics Part A, 161, 3005-3011.

[56]   Cheng, A., Hardingham, T.E. and Kimber, S.J. (2014) Generating Cartilage Repair from Pluripotent Stem Cells. Tissue Engineering Part B Reviews, 20, 257-266.

[57]   Nancarrow-Lei, R., Mafi, P., Mafi, R. and Khan, W.A. (2017) Systemic Review of Adult Mesenchymal Stem Cell Sources and Their Multilineage Differentiation Potential Relevant to Musculoskeletal Tissue Repair and Regeneration. Current Stem Cell Research and Therapy, 12, 601-610.

[58]   Scott, D.A. and Zhang, F. (2017) Implications of Human Genetic Variation in CRISPR-Based Therapeutic Genome Editing. Nature Medicine, 23, 1095-1101.

[59]   Pazoki, R. (2018) Methods for Polygenic Traits. Methods in Molecular Biology, 1793, 145-156.

[60]   Blaber, A.P., Zuj, K.A. and Goswami, N. (2013) Cerebrovascular Autoregulation: Lessons Learned from Spaceflight Research. European Journal of Applied Physiology, 113, 1909-1917.

[61]   Lenders, J.W., Eisenhofer, G., Mannelli, M. and Pacak, K. (2005) Phaeochromocytoma. The Lancet, 366, 665-675.

[62]   Henkin, S. (2016) Spontaneous Coronary Artery Dissection and Its Association with Heritable Connective Tissue Disorders. Heart, 102, 876-881.