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Vascular Ehlers-Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family.

ABSTRACT: Vascular Ehlers-Danlos Syndrome (vEDS), also known as EDS type IV, is considered to be an autosomal dominant disorder caused by sequence variants in COL3A1, which encodes the chains of type III procollagen. We identified a family in which there was marked clinical variation with the earliest death due to extensive aortic dissection at age 15 years and other family members in their eighties with no complications. The proband was born with right-sided clubfoot but was otherwise healthy until he died unexpectedly at 15 years. His sister, in addition to signs consistent with vascular EDS, had bilateral frontal and parietal polymicrogyria. The proband and his sister each had two COL3A1 sequence variants, c.1786C>T, p.(Arg596*) in exon 26 and c.3851G>A, p.(Gly1284Glu) in exon 50 on different alleles. Cells from the compound heterozygote produced a reduced amount of type III procollagen, all the chains of which had abnormal electrophoretic mobility. Biallelic sequence variants have a significantly worse outcome than heterozygous variants for either null mutations or missense mutations, and frontoparietal polymicrogyria may be an added phenotype feature. This genetic constellation provides a very rare explanation for marked intrafamilial clinical variation due to sequence variants in COL3A1.

SUBMITTER: Jorgensen A

PROVIDER: S-EPMC4795069 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Identification of two novel COL3A1 variants in patients with vascular Ehlers-Danlos syndrome.

Project description:BackgroundVascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant disease caused by aberrations in COL3A1, which encodes type III collagen. Sanger sequencing has limitations for diagnosis since exon deletion/duplication and splicing alterations are not uncommon in COL3A1. We report 2 patients with vEDS who were not diagnosed by conventional Sanger sequencing.MethodsWe performed either targeted panel or whole-genome sequencing. Complementary DNA (cDNA) sequencing was performed using cultured skin fibroblasts. Sanger sequencing of DNA was performed for the confirmation of breakpoints in the case of exon deletion. We also evaluated the sensitivity of the splicing prediction tool, SpliceAI.ResultsAn exon 27 deletion was suspected on targeted panel sequencing of 1 patient. The deletion was confirmed using cDNA sequencing (r.1870_1923del) and breakpoints were confirmed (c.1870-109_1923+10del). On targeted panel sequencing in the other patient, we found a novel intronic variant of c.1149+6T>C that leads to skipping of exon 16 (r.1051_1149del) by cDNA sequencing. SpliceAI showed 98.8% sensitivity for known splicing variants in COL3A1.ConclusionOur study highlights the necessity of a comprehensive approach to the genetic diagnosis of vEDS. In addition, cDNA sequencing was useful as an auxiliary method, especially considering the limited sensitivity of the splicing prediction tool.

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The haploinsufficient Col3a1 mouse as a model for vascular Ehlers-Danlos syndrome.

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Two closely spaced missense COL3A1 variants in cis cause vascular Ehlers-Danlos syndrome in one large Chinese family.

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A novel mutation in COL3A1 associates to vascular Ehlers-Danlos syndrome with predominant musculoskeletal involvement.

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Ehlers-Danlos Syndrome Caused by Biallelic TNXB Variants in Patients with Congenital Adrenal Hyperplasia.

Project description:Some variants that cause autosomal-recessive congenital adrenal hyperplasia (CAH) also cause hypermobility type Ehlers-Danlos syndrome (EDS) due to the monoallelic presence of a chimera disrupting two flanking genes: CYP21A2, encoding 21-hydroxylase, necessary for cortisol and aldosterone biosynthesis, and TNXB, encoding tenascin-X, an extracellular matrix protein. Two types of CAH tenascin-X (CAH-X) chimeras have been described with a total deletion of CYP21A2 and characteristic TNXB variants. CAH-X CH-1 has a TNXB exon 35 120-bp deletion resulting in haploinsufficiency, and CAH-X CH-2 has a TNXB exon 40 c.12174C>G (p.Cys4058Trp) variant resulting in a dominant-negative effect. We present here three patients with biallelic CAH-X and identify a novel dominant-negative chimera termed CAH-X CH-3. Compared with monoallelic CAH-X, biallelic CAH-X results in a more severe phenotype with skin features characteristic of classical EDS. We present evidence for disrupted tenascin-X function and computational data linking the type of TNXB variant to disease severity.

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Project description:The vascular subtype of Ehlers Danlos Syndrome (vEDS) is a rare connective tissue disorder characterized by spontaneous arterial, bowel or organ rupture. The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic variant in the alpha-1 gene of type III collagen (COL3A1) by molecular analysis. In this report, we present a case of vEDS with life threatening, spontaneous arterial dissections in association with an uncharacterized rare variant of COL3A1, exon19:c.1340G > A. Primary culture of patient skin fibroblasts followed by immunofluorescence revealed a complete absence of COL3A1 protein expression as well as altered morphology. Electron microscopy of the cultured fibroblasts showed abnormal vacuoles in the cytoplasm suggestive of a secretory defect. In this study, we have performed functional characterization of the COL3A1 exon19:c.1340G > A variant for the first time and this may now be classified as likely pathogenic in vEDS.

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Homozygosity for a null allele of COL3A1 results in recessive Ehlers-Danlos syndrome.

Project description:So far, mutations in the human COL3A1 gene have been associated with the predominantly inherited Ehlers-Danlos syndrome (EDS), vascular type. Genotype-phenotype correlation perspectives collapsed, as haploinsufficiency, which was long suggested to confer a milder or unrecognized phenotype, was reported in four patients with a phenotype similar to that of vascular EDS. Here, we study a case of recessive EDS in a young consanguineous girl of healthy parents. She fulfilled the vascular EDS criteria for laboratory testing. Total sequencing of COL3A1 cDNA identified a homozygous nucleotide duplication (c.479dupT) resulting in a premature termination codon (p.Lys161GlnfsX45). Studies in genomic DNA showed that this mutation was inherited from each parent. The expression analysis (RT-PCR, quantitative-PCR, immunohistochemistry, WB) showed strong mRNA decay and an absence of type III collagen in the proband. The expected COL3A1 haploinsufficiency in her healthy ascendants did not lead to the manifestations of vascular EDS. This case provides evidence of a stochastic effect of COL3A1 haploinsufficiency in humans, which could be explained by the relation between nonsense-mediated mRNA decay efficiency and the resulting dominant-negative effect depending on the position of the mutation and/or modifying factors. It opens up new perspectives for the understanding of COL3A1 genotype-phenotype correlations, which is required while considering targeted therapy.

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Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome.

Project description:AIMS:The vascular type of Ehlers-Danlos syndrome (EDS IV) is an autosomal-dominant disorder characterized by thin translucent skin and extensive bruising. Patients with EDS IV have reduced life expectancy (median 45-50 years) due to spontaneous rupture of arteries (particularly large arteries) or bowel. EDS IV results from mutation of the COL3A1 gene, which encodes the pro-?(1) chains of type III collagen that is secreted into the extracellular matrix, e.g. by smooth muscle cells. A mouse model of EDS IV produced by targeted ablation of Col3a1 has been of limited use as only 10% of homozygous animals survive to adulthood, whereas heterozygous animals do not die from arterial rupture. We report a novel, exploitable model of EDS IV in a spontaneously generated mouse line. METHODS AND RESULTS:Mice were identified by predisposition to sudden, unexpected death from dissection of the thoracic aorta. Aortic dissection inheritance was autosomal-dominant, presented at an early age (median, 6 weeks) with incomplete penetrance, and had a similar sex ratio bias as EDS IV (2:1, male:female). Molecular genetic analysis demonstrated that the causal mutation is a spontaneous 185 kb deletion, including the promoter region and exons 1-39, of the Col3a1 gene. As in EDS IV, aortic dissection was not associated with elevated blood pressure, aneurysm formation, or infection, but may result from aberrant collagen fibrillogenesis within the aortic wall. CONCLUSION:This novel, exploitable mouse line that faithfully models the vascular aspects of human EDS IV provides an important new tool for advancing understanding of EDS IV and of aortic dissection in general.

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