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Genetics and Genomics of Hereditary Disorders of Connective Tissue
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Genetics and Genomics of Hereditary Disorders of Connective Tissue

A topical collection in Genes (ISSN 2073-4425). This collection belongs to the section "Molecular Genetics and Genomics".

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Editors

Dr. Nazli B. Mcdonnell

E-Mail Website
Collection Editor
Veterans Administration Eastern Colorado Health System, Aurora, CO 80045, USA
Interests: Ehlers-Danlos Syndrome; aortopathy; vascular Ehlers-Danlos; fibromuscular dysplasia
Prof. Dr. Bert Callewaert

E-Mail Website
Collection Editor
University Hospital of Ghent, Ghent, Belgium
Interests: cutis laxa; arterial tortuosity syndrome; hereditary disorders of the connective tissue; congenital contractural arachnodactyly; thoracic aortic aneurysm; zebrafish and mouse models for heritable connective tissue disorders; electron microscopy
Prof. Dr. Clair A. Francomano

E-Mail Website
Collection Editor
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Interests: hereditary disorders of connective tissue; Ehlers-Danlos syndrome; skeletal dysplasias; Alström syndrome; Marfan syndrome
Dr. Philippe Khau-Van-Kien

E-Mail Website
Collection Editor
1. UF de Génétique Médicale et Cytogénétique, Centre Hospitalier Régional Universitaire de Nîmes, Nîmes, France
2. Laboratoire d'Histologie-Embryologie-Cytogénétique, Institut des Biomolécules Max Mousseron (IBMM), CNRS UMR5247, Faculté de Médecine Montpellier-Nîmes, Nîmes, France
Interests: Marfan and related disorders; familial thoracic aortic aneurysms/dissections; clinical genetics; molecular genetics; genomic medicine; developmental defects; malformation syndromes
Special Issues, Collections and Topics in MDPI journals
Dr. Yves Dulac

E-Mail Website
Collection Editor
Cardiology Pediatric Unit, CHU of Toulouse, Children Hospital, 330, Avenue Grande-Bretagne, 31059 Toulouse, France
Interests: pediatric cardiology; Marfan syndrome and related disorders; congénital cardiology; echocardiography
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

Dr. Victor McKusick coined the phrase “Hereditary Disorders of Connective Tissue” (HDCT) over 60 years ago, in a 1959 article by the same name in the Bulletin of the New York Academy of Medicine.  At that time, Dr. McKusick recognized five conditions that “appear to be hereditary and generalized derangements of one or another element of connective tissue: Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum (PXE), and Hurler syndrome.”  Today, in addition to Marfan Syndrome and  PXE, we recognize 14 different types of Ehlers-Danlos syndrome, Stickler syndrome, Beals syndrome, arterial tortuosity syndrome, and over 200 distinct skeletal dysplasias, as well as more recently recognized diagnoses such as Loeys-Dietz syndrome, all of which fall under the broad umbrella of Hereditary Disorders of Connective Tissue. 

The ubiquitous nature of connective tissue results in multi-organ involvement in these conditions, which represent Mendelian models of disease for complex traits involving bone, skin, and vasculature.  This also leads to complex multi-system presentations and may result in a prolonged diagnostic odyssey for patients. 

Molecular studies have led to an understanding of the genetic cause for most of these conditions, with a few notable exceptions, and there is a robust research community exploring the molecular pathways and pathogenesis, modifying loci and rational approaches to therapy.  Animal models for many of these conditions have been created and allow the conduct of pre-clinical therapeutic trials.  The burgeoning interest in hereditary disorders of connective tissue has led to the development of this topical collection, which will publish new findings on the HDCT.  We intend to focus on three different groups of HDCT with collections on aortopathies, elastinopathies, and skeletal dysplasias between 2021-23.  We invite you to submit original research articles, reviews, concept papers and commentaries to these topical collections. 

Dr. Nazli B. Mcdonnell
Prof. Dr. Bert Callewaert
Prof. Dr. Clair A. Francomano
Dr. Philippe Khau-Van-Kien
Dr. Yves Dulac
Collection Editors

Manuscript Submission Information

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Keywords

  • Ehlers-Danlos Syndrome
  • Marfan syndrome
  • cutis laxa
  • arterial tortuosity syndrome
  • congenital contractural arachnodactyly
  • hypermobility spectrum disorders
  • joint hypermobility
  • elastic fiber
  • collagen
  • proteoglycan
  • mouse and zebrafish modeling

Published Papers (4 papers)

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2021

Jump to: 2020

12 pages, 608 KiB  
Article
Heritable Connective Tissue Disorders in Childhood: Increased Fatigue, Pain, Disability and Decreased General Health
by Jessica Warnink-Kavelaars, Lisanne E. de Koning, Lies Rombaut, Mattijs W. Alsem, Leonie A. Menke, Jaap Oosterlaan, Annemieke I. Buizer, Raoul H. H. Engelbert and on behalf of the Pediatric Heritable Connective Tissue Disorders Study Group
Genes 2021, 12(6), 831; https://doi.org/10.3390/genes12060831 - 28 May 2021
Cited by 11 | Viewed by 4705
Abstract
Heritable Connective Tissue Disorders (HCTD) show an overlap in the physical features that can evolve in childhood. It is unclear to what extent children with HCTD experience burden of disease. This study aims to quantify fatigue, pain, disability and general health with standardized [...] Read more.
Heritable Connective Tissue Disorders (HCTD) show an overlap in the physical features that can evolve in childhood. It is unclear to what extent children with HCTD experience burden of disease. This study aims to quantify fatigue, pain, disability and general health with standardized validated questionnaires. Methods. This observational, multicenter study included 107 children, aged 4–18 years, with Marfan syndrome (MFS), 58%; Loeys-Dietz syndrome (LDS), 7%; Ehlers-Danlos syndromes (EDS), 8%; and hypermobile Ehlers-Danlos syndrome (hEDS), 27%. The assessments included PROMIS Fatigue Parent–Proxy and Pediatric self-report, pain and general health Visual-Analogue-Scales (VAS) and a Childhood Health Assessment Questionnaire (CHAQ). Results. Compared to normative data, the total HCTD-group showed significantly higher parent-rated fatigue T-scores (M = 53 (SD = 12), p = 0.004, d = 0.3), pain VAS scores (M = 2.8 (SD = 3.1), p < 0.001, d = 1.27), general health VAS scores (M = 2.5 (SD = 1.8), p < 0.001, d = 2.04) and CHAQ disability index scores (M = 0.9 (SD = 0.7), p < 0.001, d = 1.23). HCTD-subgroups showed similar results. The most adverse sequels were reported in children with hEDS, whereas the least were reported in those with MFS. Disability showed significant relationships with fatigue (p < 0.001, rs = 0.68), pain (p < 0.001, rs = 0.64) and general health (p < 0.001, rs = 0.59). Conclusions. Compared to normative data, children and adolescents with HCTD reported increased fatigue, pain, disability and decreased general health, with most differences translating into very large-sized effects. This new knowledge calls for systematic monitoring with standardized validated questionnaires, physical assessments and tailored interventions in clinical care. Full article
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16 pages, 2748 KiB  
Article
LOXL4 Abrogation Does Not Exaggerate Angiotensin II-Induced Thoracic or Abdominal Aortic Aneurysm in Mice
by Huimin Li, Jun Guo, Yiting Jia, Wei Kong and Wei Li
Genes 2021, 12(4), 513; https://doi.org/10.3390/genes12040513 - 31 Mar 2021
Cited by 7 | Viewed by 3080
Abstract
It has been shown that thoracic aortic aneurysm and dissection (TAAD) could be a Mendelian trait caused by a single gene mutation. The LOX gene mutation leads to the development of human TAAD. The LOXL4 gene is a member of the lysyl oxidase [...] Read more.
It has been shown that thoracic aortic aneurysm and dissection (TAAD) could be a Mendelian trait caused by a single gene mutation. The LOX gene mutation leads to the development of human TAAD. The LOXL4 gene is a member of the lysyl oxidase gene family. We identified seven variants in the LOXL4 gene in 219 unrelated patients with TAAD by whole-exome sequencing (WES). To further investigate whether LOXL4 is a candidate causative gene for human TAAD, a LOXL4 knockout mouse was generated, and the mutant mice were treated by subcutaneous infusion of angiotensin II. We found that abrogation of LOXL4 did not induce a more severe thoracic or abdominal aortic aneurysm compared with the wild-type C57BL/6J mice. Our results suggest that LOXL4 may not play a major role in the development of angiotensin II-induced aortic aneurysm. The functional study using this animal model system is important for the evaluation of candidate genes of TAAD identified by WES. Full article
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Graphical abstract

6 pages, 562 KiB  
Case Report
Loss-of-Function Variants in EFEMP1 Cause a Recognizable Connective Tissue Disorder Characterized by Cutis Laxa and Multiple Herniations
by Maxim Verlee, Aude Beyens, Alper Gezdirici, Elif Yilmaz Gulec, Lore Pottie, Silke De Feyter, Michiel Vanhooydonck, Piyanoot Tapaneeyaphan, Sofie Symoens and Bert Callewaert
Genes 2021, 12(4), 510; https://doi.org/10.3390/genes12040510 - 31 Mar 2021
Cited by 6 | Viewed by 2641
Abstract
Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of [...] Read more.
Hereditary disorders of connective tissue (HDCT) compromise a heterogeneous group of diseases caused by pathogenic variants in genes encoding different components of the extracellular matrix and characterized by pleiotropic manifestations, mainly affecting the cutaneous, cardiovascular, and musculoskeletal systems. We report the case of a 9-year-old boy with a discernible connective tissue disorder characterized by cutis laxa (CL) and multiple herniations and caused by biallelic loss-of-function variants in EFEMP1. Hence, we identified EFEMP1 as a novel disease-causing gene in the CL spectrum, differentiating it from other HDCT. Full article
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2020

Jump to: 2021

15 pages, 2040 KiB  
Article
Exon-Trapping Assay Improves Clinical Interpretation of COL11A1 and COL11A2 Intronic Variants in Stickler Syndrome Type 2 and Otospondylomegaepiphyseal Dysplasia
by Lucia Micale, Silvia Morlino, Annalisa Schirizzi, Emanuele Agolini, Grazia Nardella, Carmela Fusco, Stefano Castellana, Vito Guarnieri, Roberta Villa, Maria Francesca Bedeschi, Paola Grammatico, Antonio Novelli and Marco Castori
Genes 2020, 11(12), 1513; https://doi.org/10.3390/genes11121513 - 17 Dec 2020
Cited by 10 | Viewed by 3181
Abstract
Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in COL11A1 and COL11A2, respectively. In both genes, available database information indicates a [...] Read more.
Stickler syndrome (SS) is a hereditary connective tissue disorder affecting bones, eyes, and hearing. Type 2 SS and the SS variant otospondylomegaepiphyseal dysplasia (OSMED) are caused by deleterious variants in COL11A1 and COL11A2, respectively. In both genes, available database information indicates a high rate of potentially deleterious intronic variants, but published evidence of their biological effect is usually insufficient for a definite clinical interpretation. We report four previously unpublished intronic variants in COL11A1 (c.2241 + 5G>T, c.2809 − 2A>G, c.3168 + 5G>C) and COL11A2 (c.4392 + 1G>A) identified in type 2 SS/OSMED individuals. The pathogenic effect of these variants was first predicted in silico and then investigated by an exon-trapping assay. We demonstrated that all variants can induce exon in-frame deletions, which lead to the synthesis of shorter collagen XI α1 or 2 chains. Lacking residues are located in the α-triple helical region, which has a crucial role in regulating collagen fibrillogenesis. In conclusion, this study suggests that these alternative COL11A1 and COL11A2 transcripts might result in aberrant triple helix collagen. Our approach may help to improve the diagnostic molecular pathway of COL11-related disorders. Full article
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