Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations

Ritelli, Marco; Dordoni, Chiara; Venturini, Marina; Chiarelli, Nicola; Quinzani, Stefano; Traversa, Michele; Zoppi, Nicoletta; Vascellaro, Annalisa; Wischmeijer, Anita; Manfredini, Emanuela; Garavelli, Livia; Calzavara‐Pinton, Piergiacomo; Colombi, Marina

doi:10.1186/1750-1172-8-58

Cited by 103 publications

(192 citation statements)

References 38 publications

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“…Pathogenic variants in these genes were previously deemed to cause EDS classic type (Connizzo et al, 2015;Ritelli et al, 2013). Classic type EDS are rare autosomal dominant connective tissue disorders that are characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, joint hypermobility and should exclude aortic defects (Ritelli et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Zhou

Tan

et al. 2016

Sci. China Life Sci.

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Aortic dissection (AD) is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens (45 genes), MMPs/TIMPs (27 genes) in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% (64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05% (218/702) sporadic AD patients. In them, 84.86% patients (185/218) carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probably pathogenic loss-of-function (LOF) variants (20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon) in 11.06% (50/452) AD patients, which were absent in 163 controls (P=2.5×10 −5 ). Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2 −/− rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis. aortic dissection, collagen, matrix metalloproteinase, next-generation sequencing, genetic diagnosis Citation:Li, Z., Zhou, C., Tan, L., Chen, P., Cao, Y., Li, C., Li, X., Yan, J., Zeng, H., Wang, D.W., and Wang, D.W. (2017). Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissec. Sci China Life Sci 60, 57-65.

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Section: Discussionmentioning

confidence: 99%

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Zhou

Tan

et al. 2016

Sci. China Life Sci.

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“…Notably, cutaneous signs typical of cEDS (skin hyperextensibility, atrophic scars) [Ritelli et al, 2013] were absent and the patient did not fulfill the criteria to pose a clinical diagnosis of the disorder [Beighton et al, 1998]. Thus, we excluded the diagnosis of cEDS.…”

Section: Case Report and Methodsmentioning

confidence: 99%

Koolen-de Vries Syndrome: Clinical Report of an Adult and Literature Review

Ciaccio

Dordoni

Ritelli

et al. 2016

Cytogenet Genome Res

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Koolen-de Vries syndrome (KdS) is a rare genetic condition characterized by typical facial dysmorphisms, cardiac and renal defects, skeletal anomalies, developmental delay, and intellectual disability of variable level. It is caused by a 440-680-kb deletion in the 17q21.31 region, encompassing CRHR1, MAPT, IMP5, STH, and KANSL1, or by an intragenic KANSL1 mutation. The majority of the patients reported are pediatric or young adults, and long-term studies able to define the prognosis of the disease are lacking. Here, we report a patient in the fourth decade misdiagnosed in the past as classical Ehlers-Danlos syndrome for the presence of generalized joint hypermobility, who carried a 546-kb deletion in 17q21.31, and compare his phenotype with those of the few KdS adults (aged >18 years) described so far. We observed a favorable prognosis of epilepsy and cardiovascular signs and reduction of joint hypermobility with age, thus providing insight into the natural history of the disorder.

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“…Scars are commonly atrophic although do not look papyraceous. Striae distensae and pyezogenic papules are present in EDS classic and hypermobile types [6,12]. Absence of the lingual or inferior labial frenulum was recently reported in EDS hypermobile type [13,14].…”

Section: Doimentioning

confidence: 98%

“…In EDS classic type, mutations are often disclosed in the COL5 gene [5,6]. The COL3 gene is commonly disturbed in the EDS vascular type [7].…”

Section: Ehlers-danlos Syndrome Classificationmentioning

confidence: 99%

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Gynecologic and obstetric impact of the ehlers-danlos syndrome : clues from scrutinizing dermal ultrastructural alterations

Hermanns‐Lê¹,

Pierard²,

Piérard-Franchimont³

et al. 2014

Gynecol

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Background: The Ehlers-Danlos syndrome (EDS) represents a heterogenous group of heritable connective tissue disorders chiefly characterized by joint laxity, increased skin distensibility and connective tissue fragility. Each EDS type corresponds to a multisystemic disorder with widespread implications. Physicians evoke the EDS diagnosis in presence of some typical cutaneous signs, such as atrophic scars and frequent hematomas. Methods: To revisit the transmission electron microscopy support from skin biopsies when screening EDS in gynecologyobstetrics. Results: EDS women commonly suffer from a series of gynecologic and obstetric disorders. Dermal ultrastructural changes are keynote features suggesting some EDS types. Conclusion: Gene mutations are mostly identified in the classic and vascular EDS types, but only in sporadic cases of the hypermobile EDS type which apparently represents the most frequent type. Dermal ultrastructural changes represent relevant diagnostic clues for the practitioner. Preconception counseling about possible complications is welcome. Management requires precise diagnosis of the EDS type.

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Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations

Cited by 103 publications

References 38 publications

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Koolen-de Vries Syndrome: Clinical Report of an Adult and Literature Review

Gynecologic and obstetric impact of the ehlers-danlos syndrome : clues from scrutinizing dermal ultrastructural alterations

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