Mutation in TNXB gene causes moderate to severe Ehlers-Danlos syndrome

Kaufman, Carolyn S.; Butler, Merlin G.

doi:10.5496/wjmg.v6.i2.17

Cited by 20 publications

(16 citation statements)

References 11 publications

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“…None of them were rejected based on assessed quality alone, so that a large population could be obtained, based on which it is possible to draw firm conclusions. These 112 papers report on 467 patients (197 males, 238 females, and 32 not defined) from 342 unrelated families, and include 29 papers on classical EDS (cEDS; COL5A1/2 : n = 25; COL1A1 p.(Arg312Cys): n =4), 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 6 on classical-like EDS (clEDS; TNXB ), 52 , 53 , 54 , 55 , 56 , 57 three on cardiac-valvular EDS (cvEDS; COL1A2 ), 58 , 59 , 60 ten on arthrochalasia EDS (aEDS; COL1A1/2 ), 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 six on dermatosparaxis EDS (dEDS; ADAMTS2 ), 71 , 72 , 73 , 74 , 75 , 76 22 on kyphoscoliotic EDS (kEDS; PLOD1 : n = 17, FKBP14 : n = 5), 4 , 77 , ...…”

Section: Resultsmentioning

confidence: 99%

Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review

D’hondt

Damme

Malfait

2018

Genetics in Medicine

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PurposeWithin the spectrum of the Ehlers-Danlos syndromes (EDS), vascular complications are usually associated with the vascular subtype of EDS. Vascular complications are also observed in other EDS subtypes, but the reports are anecdotal and the information is dispersed. To better document the nature of vascular complications among “nonvascular” EDS subtypes, we performed a systematic review.MethodsWe queried three databases for English-language studies from inception until May 2017, documenting both phenotypes and genotypes of patients with nonvascular EDS subtypes. The outcome included the number and nature of vascular complications.ResultsA total of 112 papers were included and data were collected from 467 patients, of whom 77 presented with a vascular phenotype. Severe complications included mainly hematomas (53%), frequently reported in musculocontractural and classical-like EDS; intracranial hemorrhages (18%), with a high risk in dermatosparaxis EDS; and arterial dissections (16%), frequently reported in kyphoscoliotic and classical EDS. Other, more minor, vascular complications were reported in cardiac-valvular, arthrochalasia, spondylodysplastic, and periodontal EDS.ConclusionPotentially life-threatening vascular complications are a rare but important finding in several nonvascular EDS subtypes, highlighting a need for more systematic documentation. This review will help familiarize clinicians with the spectrum of vascular complications in EDS and guide follow-up and management.

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Section: Resultsmentioning

confidence: 99%

Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review

D’hondt

Damme

Malfait

2018

Genetics in Medicine

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“…However, in some patients, missense variants were also reported to cause the classical‐like EDS phenotype (Pénisson‐Besnier et al . ; Kaufman & Butler ). The variants identified in the affected dog both lead to amino acid substitutions: p.(Ser671Asn) is located in one of multiple EGF‐like domains and p.(Gly967Asp) in one of multiple fibronectin type 3 modules.…”

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confidence: 99%

Compound heterozygosity for TNXB genetic variants in a mixed‐breed dog with Ehlers‐Danlos syndrome

et al. 2019

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Summary The Ehlers‐Danlos syndromes (EDSs) are a heterogeneous group of inherited connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and tissue fragility. Inherited disorders similar to human EDS have been reported in different mammalian species. In the present study, we investigated a female mixed‐breed dog with clinical signs of EDS. Whole‐genome sequencing of the affected dog revealed two missense variants in the TNXB gene, encoding the extracellular matrix protein tenascin XB. In humans, TNXB genetic variants cause classical‐like EDS or the milder hypermobile EDS. The affected dog was heterozygous at both identified variants. Each variant allele was transmitted from one of the case's parents, consistent with compound heterozygosity. Although one of the variant alleles, XM_003431680.3:c.2012G>A, p.(Ser671Asn), was private to the family of the affected dog and absent from whole‐genome sequencing data of 599 control dogs, the second variant allele, XM_003431680.3:c.2900G>A, p.(Gly967Asp), is present at a low frequency in the Chihuahua and Poodle population. Given that TNXB is a functional candidate gene for EDS, we suggest that compound heterozygosity for the identified TNXB variants may have caused the EDS‐like phenotype in the affected dog. Chihuahuas and Poodles should be monitored for EDS cases, which might confirm the hypothesized pathogenic effect of the segregating TNXB variant.

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“…These variants are frameshift (7/15), stop codon (4/15), or splicing (2/15) and lead to the insertion of a premature stop codon with a presumed loss of expression of the protein. Two out of these 15 variants (2/15) are missense which have detrimental effects on the proper protein folding and stability [10,13]. Among the 15 variants, 11 are identified in single patients/families.…”

Section: Discussionmentioning

confidence: 99%

Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome

Micale

Guarnieri

Augello

et al. 2019

Genes

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TNXB-related classical-like Ehlers-Danlos syndrome (TNXB-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic null variants in TNXB, encoding tenascin-X. Less than 30 individuals have been reported to date, mostly of Dutch origin and showing a phenotype resembling classical Ehlers-Danlos syndrome without atrophic scarring. TNXB-clEDS is likely underdiagnosed due to the complex structure of the TNXB locus, a fact that complicates diagnostic molecular testing. Here, we report two unrelated Italian women with TNXB-clEDS due to compound heterozygosity for null alleles in TNXB. Both presented soft and hyperextensible skin, generalized joint hypermobility and related musculoskeletal complications, and chronic constipation. In addition, individual 1 showed progressive finger contractures and shortened metatarsals, while individual 2 manifested recurrent subconjunctival hemorrhages and an event of spontaneous rupture of the brachial vein. Molecular testing found the two previously unreported c.8278C > T p.(Gln2760*) and the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variants in Individual 1, and the novel c.1150dupG p.(Glu384Glyfs*57) and the recurrent c.11435_11524+30del variants in Individual 2. mRNA analysis confirmed that the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variant causes a frameshift leading to a predicted truncated protein [p.(Thr787Glyfs*40)]. This study refines the phenotype recently delineated in association with biallelic null alleles in TNXB, and adds three novel variants to its mutational repertoire. Unusual digital anomalies seem confirmed as possibly peculiar of TNXB-clEDS, while vascular fragility could be more than a chance association also in this Ehlers-Danlos syndrome type.

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Mutation in TNXB gene causes moderate to severe Ehlers-Danlos syndrome

Cited by 20 publications

References 11 publications

Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review

Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: a systematic review

Compound heterozygosity for TNXB genetic variants in a mixed‐breed dog with Ehlers‐Danlos syndrome

Novel TNXB Variants in Two Italian Patients with Classical-Like Ehlers-Danlos Syndrome

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