Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations
Identifieur interne : 002437 ( Pmc/Checkpoint ); précédent : 002436; suivant : 002438Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations
Auteurs : Marco Ritelli [Italie] ; Chiara Dordoni [Italie] ; Marina Venturini [Italie] ; Nicola Chiarelli [Italie] ; Stefano Quinzani [Italie] ; Michele Traversa [Italie] ; Nicoletta Zoppi [Italie] ; Annalisa Vascellaro [Italie] ; Anita Wischmeijer [Italie] ; Emanuela Manfredini [Italie] ; Livia Garavelli [Italie] ; Piergiacomo Calzavara-Pinton [Italie] ; Marina Colombi [Italie]Source :
- Orphanet Journal of Rare Diseases [ 1750-1172 ] ; 2013.
Abstract
Classic Ehlers–Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect.
This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the
We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands,
Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical diagnosis in the large majority of the patients. The borderline patients for whom these criteria fail can be diagnosed when minor signs of connective tissue diseases and family history are present and when genetic testing reveals a defect in COLLV. Our data also confirm that
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DOI: 10.1186/1750-1172-8-58
PubMed: 23587214
PubMed Central: 3653713
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<author><name sortKey="Zoppi, Nicoletta" sort="Zoppi, Nicoletta" uniqKey="Zoppi N" first="Nicoletta" last="Zoppi">Nicoletta Zoppi</name>
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<author><name sortKey="Vascellaro, Annalisa" sort="Vascellaro, Annalisa" uniqKey="Vascellaro A" first="Annalisa" last="Vascellaro">Annalisa Vascellaro</name>
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<author><name sortKey="Manfredini, Emanuela" sort="Manfredini, Emanuela" uniqKey="Manfredini E" first="Emanuela" last="Manfredini">Emanuela Manfredini</name>
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<author><name sortKey="Garavelli, Livia" sort="Garavelli, Livia" uniqKey="Garavelli L" first="Livia" last="Garavelli">Livia Garavelli</name>
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<author><name sortKey="Colombi, Marina" sort="Colombi, Marina" uniqKey="Colombi M" first="Marina" last="Colombi">Marina Colombi</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 <italic>COL5A1</italic>
and 2 <italic>COL5A2</italic>
novel mutations</title>
<author><name sortKey="Ritelli, Marco" sort="Ritelli, Marco" uniqKey="Ritelli M" first="Marco" last="Ritelli">Marco Ritelli</name>
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<author><name sortKey="Dordoni, Chiara" sort="Dordoni, Chiara" uniqKey="Dordoni C" first="Chiara" last="Dordoni">Chiara Dordoni</name>
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<author><name sortKey="Venturini, Marina" sort="Venturini, Marina" uniqKey="Venturini M" first="Marina" last="Venturini">Marina Venturini</name>
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<author><name sortKey="Chiarelli, Nicola" sort="Chiarelli, Nicola" uniqKey="Chiarelli N" first="Nicola" last="Chiarelli">Nicola Chiarelli</name>
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<author><name sortKey="Quinzani, Stefano" sort="Quinzani, Stefano" uniqKey="Quinzani S" first="Stefano" last="Quinzani">Stefano Quinzani</name>
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</affiliation>
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<author><name sortKey="Traversa, Michele" sort="Traversa, Michele" uniqKey="Traversa M" first="Michele" last="Traversa">Michele Traversa</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia</wicri:regionArea>
<wicri:noRegion>25123 Brescia</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Zoppi, Nicoletta" sort="Zoppi, Nicoletta" uniqKey="Zoppi N" first="Nicoletta" last="Zoppi">Nicoletta Zoppi</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia</wicri:regionArea>
<wicri:noRegion>25123 Brescia</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Vascellaro, Annalisa" sort="Vascellaro, Annalisa" uniqKey="Vascellaro A" first="Annalisa" last="Vascellaro">Annalisa Vascellaro</name>
<affiliation wicri:level="1"><nlm:aff id="I2">Department of Dermatology, University Hospital Spedali Civili, Brescia, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Dermatology, University Hospital Spedali Civili, Brescia</wicri:regionArea>
<wicri:noRegion>Brescia</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Wischmeijer, Anita" sort="Wischmeijer, Anita" uniqKey="Wischmeijer A" first="Anita" last="Wischmeijer">Anita Wischmeijer</name>
<affiliation wicri:level="1"><nlm:aff id="I3">Clinical Genetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S. Maria Nuova, Reggio Emilia, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Clinical Genetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S. Maria Nuova, Reggio Emilia</wicri:regionArea>
<wicri:noRegion>Reggio Emilia</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="I4">Department of Medical Genetics, Policlinico Sant’Orsola-Malpighi, University of Bologna, Bologna, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Medical Genetics, Policlinico Sant’Orsola-Malpighi, University of Bologna, Bologna</wicri:regionArea>
<wicri:noRegion>Bologna</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Manfredini, Emanuela" sort="Manfredini, Emanuela" uniqKey="Manfredini E" first="Emanuela" last="Manfredini">Emanuela Manfredini</name>
<affiliation wicri:level="3"><nlm:aff id="I5">Dipartimento Materno Infantile, Ospedale Niguarda Ca’ Granda, Milan, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Dipartimento Materno Infantile, Ospedale Niguarda Ca’ Granda, Milan</wicri:regionArea>
<placeName><settlement type="city">Milan</settlement>
<region nuts="2">Lombardie</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Garavelli, Livia" sort="Garavelli, Livia" uniqKey="Garavelli L" first="Livia" last="Garavelli">Livia Garavelli</name>
<affiliation wicri:level="1"><nlm:aff id="I3">Clinical Genetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S. Maria Nuova, Reggio Emilia, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Clinical Genetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S. Maria Nuova, Reggio Emilia</wicri:regionArea>
<wicri:noRegion>Reggio Emilia</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Calzavara Pinton, Piergiacomo" sort="Calzavara Pinton, Piergiacomo" uniqKey="Calzavara Pinton P" first="Piergiacomo" last="Calzavara-Pinton">Piergiacomo Calzavara-Pinton</name>
<affiliation wicri:level="1"><nlm:aff id="I2">Department of Dermatology, University Hospital Spedali Civili, Brescia, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Dermatology, University Hospital Spedali Civili, Brescia</wicri:regionArea>
<wicri:noRegion>Brescia</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Colombi, Marina" sort="Colombi, Marina" uniqKey="Colombi M" first="Marina" last="Colombi">Marina Colombi</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia</wicri:regionArea>
<wicri:noRegion>25123 Brescia</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series><title level="j">Orphanet Journal of Rare Diseases</title>
<idno type="eISSN">1750-1172</idno>
<imprint><date when="2013">2013</date>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Classic Ehlers–Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect.</p>
</sec>
<sec><title>Methods</title>
<p>This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the <italic>COL5A1</italic>
gene and, if no mutation was detected, <italic>COL5A2</italic>
analysis. In the negative patients the presence of large genomic rearrangements in <italic>COL5A1</italic>
was investigated using MLPA, and positive results were confirmed via SNP-array analysis.</p>
</sec>
<sec><title>Results</title>
<p>We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands, <italic>COL5A1</italic>
or <italic>COL5A2</italic>
mutations were detected. Twenty-one mutations were in the <italic>COL5A1</italic>
gene, 18 of which were novel (2 recurrent). Of these, 16 mutations led to nonsense-mediated mRNA decay (NMD) and to COLLV haploinsufficiency and 5 mutations were structural. Two novel <italic>COL5A2</italic>
splice mutations were detected in patients with the most severe phenotypes. The known p. (Arg312Cys) mutation in the <italic>COL1A1</italic>
gene was identified in one patient with vascular-like cEDS.</p>
</sec>
<sec><title>Conclusions</title>
<p>Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical diagnosis in the large majority of the patients. The borderline patients for whom these criteria fail can be diagnosed when minor signs of connective tissue diseases and family history are present and when genetic testing reveals a defect in COLLV. Our data also confirm that <italic>COL5A1</italic>
and <italic>COL5A2</italic>
are the major, if not the only, genes involved in cEDS.</p>
</sec>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Steinmann, B" uniqKey="Steinmann B">B Steinmann</name>
</author>
<author><name sortKey="Royce, Pm" uniqKey="Royce P">PM Royce</name>
</author>
<author><name sortKey="Superti Furga, A" uniqKey="Superti Furga A">A Superti-Furga</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Beighton, P" uniqKey="Beighton P">P Beighton</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
<author><name sortKey="Steinmann, B" uniqKey="Steinmann B">B Steinmann</name>
</author>
<author><name sortKey="Tsipouras, P" uniqKey="Tsipouras P">P Tsipouras</name>
</author>
<author><name sortKey="Wenstrup, Rj" uniqKey="Wenstrup R">RJ Wenstrup</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Wenstrup, R" uniqKey="Wenstrup R">R Wenstrup</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Coucke, P" uniqKey="Coucke P">P Coucke</name>
</author>
<author><name sortKey="Symoens, S" uniqKey="Symoens S">S Symoens</name>
</author>
<author><name sortKey="Loeys, B" uniqKey="Loeys B">B Loeys</name>
</author>
<author><name sortKey="Nuytinck, L" uniqKey="Nuytinck L">L Nuytinck</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Wenstrup, Rj" uniqKey="Wenstrup R">RJ Wenstrup</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
<author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wenstrup, Rj" uniqKey="Wenstrup R">RJ Wenstrup</name>
</author>
<author><name sortKey="Meyer, Ra" uniqKey="Meyer R">RA Meyer</name>
</author>
<author><name sortKey="Lyle, Js" uniqKey="Lyle J">JS Lyle</name>
</author>
<author><name sortKey="Hoechstetter, L" uniqKey="Hoechstetter L">L Hoechstetter</name>
</author>
<author><name sortKey="Rose, Ps" uniqKey="Rose P">PS Rose</name>
</author>
<author><name sortKey="Levy, Hp" uniqKey="Levy H">HP Levy</name>
</author>
<author><name sortKey="Francomano, Ca" uniqKey="Francomano C">CA Francomano</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Borck, G" uniqKey="Borck G">G Borck</name>
</author>
<author><name sortKey="Beighton, P" uniqKey="Beighton P">P Beighton</name>
</author>
<author><name sortKey="Wilhelm, C" uniqKey="Wilhelm C">C Wilhelm</name>
</author>
<author><name sortKey="Kohlhase, J" uniqKey="Kohlhase J">J Kohlhase</name>
</author>
<author><name sortKey="Kubisch, C" uniqKey="Kubisch C">C Kubisch</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Leeuw, K" uniqKey="De Leeuw K">K de Leeuw</name>
</author>
<author><name sortKey="Goorhuis, Jf" uniqKey="Goorhuis J">JF Goorhuis</name>
</author>
<author><name sortKey="Tielliu, If" uniqKey="Tielliu I">IF Tielliu</name>
</author>
<author><name sortKey="Symoens, S" uniqKey="Symoens S">S Symoens</name>
</author>
<author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A de Paepe</name>
</author>
<author><name sortKey="Van Tintelen, Jp" uniqKey="Van Tintelen J">JP van Tintelen</name>
</author>
<author><name sortKey="Hulscher, Jb" uniqKey="Hulscher J">JB Hulscher</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Levy, Hp" uniqKey="Levy H">HP Levy</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mayer, K" uniqKey="Mayer K">K Mayer</name>
</author>
<author><name sortKey="Kennerknecht, I" uniqKey="Kennerknecht I">I Kennerknecht</name>
</author>
<author><name sortKey="Steinmann, B" uniqKey="Steinmann B">B Steinmann</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fichard, A" uniqKey="Fichard A">A Fichard</name>
</author>
<author><name sortKey="Tillet, E" uniqKey="Tillet E">E Tillet</name>
</author>
<author><name sortKey="Delacoux, F" uniqKey="Delacoux F">F Delacoux</name>
</author>
<author><name sortKey="Garrone, R" uniqKey="Garrone R">R Garrone</name>
</author>
<author><name sortKey="Ruggiero, F" uniqKey="Ruggiero F">F Ruggiero</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Birk, De" uniqKey="Birk D">DE Birk</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Unsold, C" uniqKey="Unsold C">C Unsöld</name>
</author>
<author><name sortKey="Pappano, Wn" uniqKey="Pappano W">WN Pappano</name>
</author>
<author><name sortKey="Imamura, Y" uniqKey="Imamura Y">Y Imamura</name>
</author>
<author><name sortKey="Steiglitz, Bm" uniqKey="Steiglitz B">BM Steiglitz</name>
</author>
<author><name sortKey="Greenspan, Ds" uniqKey="Greenspan D">DS Greenspan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Smith, Sm" uniqKey="Smith S">SM Smith</name>
</author>
<author><name sortKey="Birk, De" uniqKey="Birk D">DE Birk</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Symoens, S" uniqKey="Symoens S">S Symoens</name>
</author>
<author><name sortKey="Renard, M" uniqKey="Renard M">M Renard</name>
</author>
<author><name sortKey="Bonod Bidaud, C" uniqKey="Bonod Bidaud C">C Bonod Bidaud</name>
</author>
<author><name sortKey="Syx, D" uniqKey="Syx D">D Syx</name>
</author>
<author><name sortKey="Vaganay, E" uniqKey="Vaganay E">E Vaganay</name>
</author>
<author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Ricard Blum, S" uniqKey="Ricard Blum S">S Ricard-Blum</name>
</author>
<author><name sortKey="Kessler, E" uniqKey="Kessler E">E Kessler</name>
</author>
<author><name sortKey="Van Laer, L" uniqKey="Van Laer L">L Van Laer</name>
</author>
<author><name sortKey="Coucke, P" uniqKey="Coucke P">P Coucke</name>
</author>
<author><name sortKey="Ruggiero, F" uniqKey="Ruggiero F">F Ruggiero</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hausser, I" uniqKey="Hausser I">I Hausser</name>
</author>
<author><name sortKey="Anton Lamprecht, I" uniqKey="Anton Lamprecht I">I Anton-Lamprecht</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Symoens, S" uniqKey="Symoens S">S Symoens</name>
</author>
<author><name sortKey="Syx, D" uniqKey="Syx D">D Syx</name>
</author>
<author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Callewaert, B" uniqKey="Callewaert B">B Callewaert</name>
</author>
<author><name sortKey="De Backer, J" uniqKey="De Backer J">J De Backer</name>
</author>
<author><name sortKey="Vanakker, O" uniqKey="Vanakker O">O Vanakker</name>
</author>
<author><name sortKey="Coucke, P" uniqKey="Coucke P">P Coucke</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dalgleish, R" uniqKey="Dalgleish R">R Dalgleish</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Toriello, Hv" uniqKey="Toriello H">HV Toriello</name>
</author>
<author><name sortKey="Glover, Tw" uniqKey="Glover T">TW Glover</name>
</author>
<author><name sortKey="Takahara, K" uniqKey="Takahara K">K Takahara</name>
</author>
<author><name sortKey="Byers, Ph" uniqKey="Byers P">PH Byers</name>
</author>
<author><name sortKey="Miller, De" uniqKey="Miller D">DE Miller</name>
</author>
<author><name sortKey="Higgins, Jv" uniqKey="Higgins J">JV Higgins</name>
</author>
<author><name sortKey="Greenspan, Ds" uniqKey="Greenspan D">DS Greenspan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
<author><name sortKey="Nuytinck, L" uniqKey="Nuytinck L">L Nuytinck</name>
</author>
<author><name sortKey="Hausser, I" uniqKey="Hausser I">I Hausser</name>
</author>
<author><name sortKey="Anton Lamprecht, I" uniqKey="Anton Lamprecht I">I Anton-Lamprecht</name>
</author>
<author><name sortKey="Naeyaert, Jm" uniqKey="Naeyaert J">JM Naeyaert</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schwarze, U" uniqKey="Schwarze U">U Schwarze</name>
</author>
<author><name sortKey="Atkinson, M" uniqKey="Atkinson M">M Atkinson</name>
</author>
<author><name sortKey="Hoffman, Gg" uniqKey="Hoffman G">GG Hoffman</name>
</author>
<author><name sortKey="Greenspan, Ds" uniqKey="Greenspan D">DS Greenspan</name>
</author>
<author><name sortKey="Byers, Ph" uniqKey="Byers P">PH Byers</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wenstrup, Rj" uniqKey="Wenstrup R">RJ Wenstrup</name>
</author>
<author><name sortKey="Florer, Jb" uniqKey="Florer J">JB Florer</name>
</author>
<author><name sortKey="Willing, Mc" uniqKey="Willing M">MC Willing</name>
</author>
<author><name sortKey="Giunta, C" uniqKey="Giunta C">C Giunta</name>
</author>
<author><name sortKey="Steinmann, B" uniqKey="Steinmann B">B Steinmann</name>
</author>
<author><name sortKey="Young, F" uniqKey="Young F">F Young</name>
</author>
<author><name sortKey="Susic, M" uniqKey="Susic M">M Susic</name>
</author>
<author><name sortKey="Cole, Wg" uniqKey="Cole W">WG Cole</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Matyas, G" uniqKey="Matyas G">G Mátyás</name>
</author>
<author><name sortKey="Giunta, C" uniqKey="Giunta C">C Giunta</name>
</author>
<author><name sortKey="Steinmann, B" uniqKey="Steinmann B">B Steinmann</name>
</author>
<author><name sortKey="Hossle, Jp" uniqKey="Hossle J">JP Hossle</name>
</author>
<author><name sortKey="Hellwig, R" uniqKey="Hellwig R">R Hellwig</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Segev, F" uniqKey="Segev F">F Segev</name>
</author>
<author><name sortKey="Heon, E" uniqKey="Heon E">E Héon</name>
</author>
<author><name sortKey="Cole, Wg" uniqKey="Cole W">WG Cole</name>
</author>
<author><name sortKey="Wenstrup, Rj" uniqKey="Wenstrup R">RJ Wenstrup</name>
</author>
<author><name sortKey="Young, F" uniqKey="Young F">F Young</name>
</author>
<author><name sortKey="Slomovic, Ar" uniqKey="Slomovic A">AR Slomovic</name>
</author>
<author><name sortKey="Rootman, Ds" uniqKey="Rootman D">DS Rootman</name>
</author>
<author><name sortKey="Whitaker Menezes, D" uniqKey="Whitaker Menezes D">D Whitaker-Menezes</name>
</author>
<author><name sortKey="Chervoneva, I" uniqKey="Chervoneva I">I Chervoneva</name>
</author>
<author><name sortKey="Birk, De" uniqKey="Birk D">DE Birk</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mitchell, Al" uniqKey="Mitchell A">AL Mitchell</name>
</author>
<author><name sortKey="Schwarze, U" uniqKey="Schwarze U">U Schwarze</name>
</author>
<author><name sortKey="Jennings, Jf" uniqKey="Jennings J">JF Jennings</name>
</author>
<author><name sortKey="Byers, Ph" uniqKey="Byers P">PH Byers</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bouma, P" uniqKey="Bouma P">P Bouma</name>
</author>
<author><name sortKey="Cabral, Wa" uniqKey="Cabral W">WA Cabral</name>
</author>
<author><name sortKey="Cole, Wg" uniqKey="Cole W">WG Cole</name>
</author>
<author><name sortKey="Marini, Jc" uniqKey="Marini J">JC Marini</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wenstrup, Rj" uniqKey="Wenstrup R">RJ Wenstrup</name>
</author>
<author><name sortKey="Langland, Gt" uniqKey="Langland G">GT Langland</name>
</author>
<author><name sortKey="Willing, Mc" uniqKey="Willing M">MC Willing</name>
</author>
<author><name sortKey="D Ouza, Vn" uniqKey="D Ouza V">VN D’Souza</name>
</author>
<author><name sortKey="Cole, Wg" uniqKey="Cole W">WG Cole</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nicholls, Ac" uniqKey="Nicholls A">AC Nicholls</name>
</author>
<author><name sortKey="Oliver, Je" uniqKey="Oliver J">JE Oliver</name>
</author>
<author><name sortKey="Mccarron, S" uniqKey="Mccarron S">S McCarron</name>
</author>
<author><name sortKey="Harrison, Jb" uniqKey="Harrison J">JB Harrison</name>
</author>
<author><name sortKey="Greenspan, Ds" uniqKey="Greenspan D">DS Greenspan</name>
</author>
<author><name sortKey="Pope, Fm" uniqKey="Pope F">FM Pope</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Michalickova, K" uniqKey="Michalickova K">K Michalickova</name>
</author>
<author><name sortKey="Susic, M" uniqKey="Susic M">M Susic</name>
</author>
<author><name sortKey="Willing, Mc" uniqKey="Willing M">MC Willing</name>
</author>
<author><name sortKey="Wenstrup, Rj" uniqKey="Wenstrup R">RJ Wenstrup</name>
</author>
<author><name sortKey="Cole, Wg" uniqKey="Cole W">WG Cole</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Richards, Aj" uniqKey="Richards A">AJ Richards</name>
</author>
<author><name sortKey="Martin, S" uniqKey="Martin S">S Martin</name>
</author>
<author><name sortKey="Nicholls, Ac" uniqKey="Nicholls A">AC Nicholls</name>
</author>
<author><name sortKey="Harrison, Jb" uniqKey="Harrison J">JB Harrison</name>
</author>
<author><name sortKey="Pope, Fm" uniqKey="Pope F">FM Pope</name>
</author>
<author><name sortKey="Burrows, Np" uniqKey="Burrows N">NP Burrows</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Symoens, S" uniqKey="Symoens S">S Symoens</name>
</author>
<author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Renard, M" uniqKey="Renard M">M Renard</name>
</author>
<author><name sortKey="Andre, J" uniqKey="Andre J">J Andre</name>
</author>
<author><name sortKey="Hausser, I" uniqKey="Hausser I">I Hausser</name>
</author>
<author><name sortKey="Loeys, B" uniqKey="Loeys B">B Loeys</name>
</author>
<author><name sortKey="Coucke, P" uniqKey="Coucke P">P Coucke</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Takahara, K" uniqKey="Takahara K">K Takahara</name>
</author>
<author><name sortKey="Schwarze, U" uniqKey="Schwarze U">U Schwarze</name>
</author>
<author><name sortKey="Imamura, Y" uniqKey="Imamura Y">Y Imamura</name>
</author>
<author><name sortKey="Hoffman, Gg" uniqKey="Hoffman G">GG Hoffman</name>
</author>
<author><name sortKey="Toriello, H" uniqKey="Toriello H">H Toriello</name>
</author>
<author><name sortKey="Smith, Lt" uniqKey="Smith L">LT Smith</name>
</author>
<author><name sortKey="Byers, Ph" uniqKey="Byers P">PH Byers</name>
</author>
<author><name sortKey="Greenspan, Ds" uniqKey="Greenspan D">DS Greenspan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Symoens, S" uniqKey="Symoens S">S Symoens</name>
</author>
<author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Vlummens, P" uniqKey="Vlummens P">P Vlummens</name>
</author>
<author><name sortKey="Hermanns Le, T" uniqKey="Hermanns Le T">T Hermanns-Le</name>
</author>
<author><name sortKey="Syx, D" uniqKey="Syx D">D Syx</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nuytinck, L" uniqKey="Nuytinck L">L Nuytinck</name>
</author>
<author><name sortKey="Freund, M" uniqKey="Freund M">M Freund</name>
</author>
<author><name sortKey="Lagae, L" uniqKey="Lagae L">L Lagae</name>
</author>
<author><name sortKey="Pierard, Ge" uniqKey="Pierard G">GE Pierard</name>
</author>
<author><name sortKey="Hermanns Le, T" uniqKey="Hermanns Le T">T Hermanns-Le</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schalkwijk, J" uniqKey="Schalkwijk J">J Schalkwijk</name>
</author>
<author><name sortKey="Zweers, Mc" uniqKey="Zweers M">MC Zweers</name>
</author>
<author><name sortKey="Steijlen, Pm" uniqKey="Steijlen P">PM Steijlen</name>
</author>
<author><name sortKey="Dean, Wb" uniqKey="Dean W">WB Dean</name>
</author>
<author><name sortKey="Taylor, G" uniqKey="Taylor G">G Taylor</name>
</author>
<author><name sortKey="Van Vlijmen, Im" uniqKey="Van Vlijmen I">IM van Vlijmen</name>
</author>
<author><name sortKey="Van Haren, B" uniqKey="Van Haren B">B van Haren</name>
</author>
<author><name sortKey="Miller, Wl" uniqKey="Miller W">WL Miller</name>
</author>
<author><name sortKey="Bristow, J" uniqKey="Bristow J">J Bristow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Malfait, F" uniqKey="Malfait F">F Malfait</name>
</author>
<author><name sortKey="Symoens, S" uniqKey="Symoens S">S Symoens</name>
</author>
<author><name sortKey="De Backer, J" uniqKey="De Backer J">J De Backer</name>
</author>
<author><name sortKey="Hermanns Le, T" uniqKey="Hermanns Le T">T Hermanns-Lê</name>
</author>
<author><name sortKey="Sakalihasan, N" uniqKey="Sakalihasan N">N Sakalihasan</name>
</author>
<author><name sortKey="Lapiere, Cm" uniqKey="Lapiere C">CM Lapière</name>
</author>
<author><name sortKey="Coucke, P" uniqKey="Coucke P">P Coucke</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zoppi, N" uniqKey="Zoppi N">N Zoppi</name>
</author>
<author><name sortKey="Gardella, R" uniqKey="Gardella R">R Gardella</name>
</author>
<author><name sortKey="De Paepe, A" uniqKey="De Paepe A">A De Paepe</name>
</author>
<author><name sortKey="Barlati, S" uniqKey="Barlati S">S Barlati</name>
</author>
<author><name sortKey="Colombi, M" uniqKey="Colombi M">M Colombi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Venselaar, H" uniqKey="Venselaar H">H Venselaar</name>
</author>
<author><name sortKey="Te Beek, Tah" uniqKey="Te Beek T">TAH Te Beek</name>
</author>
<author><name sortKey="Kuipers, Rkp" uniqKey="Kuipers R">RKP Kuipers</name>
</author>
<author><name sortKey="Hekkelman, Ml" uniqKey="Hekkelman M">ML Hekkelman</name>
</author>
<author><name sortKey="Vriend, G" uniqKey="Vriend G">G Vriend</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Castori, M" uniqKey="Castori M">M Castori</name>
</author>
<author><name sortKey="Morlino, S" uniqKey="Morlino S">S Morlino</name>
</author>
<author><name sortKey="Celletti, C" uniqKey="Celletti C">C Celletti</name>
</author>
<author><name sortKey="Celli, M" uniqKey="Celli M">M Celli</name>
</author>
<author><name sortKey="Morrone, A" uniqKey="Morrone A">A Morrone</name>
</author>
<author><name sortKey="Colombi, M" uniqKey="Colombi M">M Colombi</name>
</author>
<author><name sortKey="Camerota, F" uniqKey="Camerota F">F Camerota</name>
</author>
<author><name sortKey="Grammatico, P" uniqKey="Grammatico P">P Grammatico</name>
</author>
</analytic>
</biblStruct>
</listBibl>
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</TEI>
<pmc article-type="research-article" xml:lang="en"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Orphanet J Rare Dis</journal-id>
<journal-id journal-id-type="iso-abbrev">Orphanet J Rare Dis</journal-id>
<journal-title-group><journal-title>Orphanet Journal of Rare Diseases</journal-title>
</journal-title-group>
<issn pub-type="epub">1750-1172</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23587214</article-id>
<article-id pub-id-type="pmc">3653713</article-id>
<article-id pub-id-type="publisher-id">1750-1172-8-58</article-id>
<article-id pub-id-type="doi">10.1186/1750-1172-8-58</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 <italic>COL5A1</italic>
and 2 <italic>COL5A2</italic>
novel mutations</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="A1"><name><surname>Ritelli</surname>
<given-names>Marco</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>ritelli@med.unibs.it</email>
</contrib>
<contrib contrib-type="author" id="A2"><name><surname>Dordoni</surname>
<given-names>Chiara</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>chiara.dordoni@hotmail.it</email>
</contrib>
<contrib contrib-type="author" id="A3"><name><surname>Venturini</surname>
<given-names>Marina</given-names>
</name>
<xref ref-type="aff" rid="I2">2</xref>
<email>marinaventurini@libero.it</email>
</contrib>
<contrib contrib-type="author" id="A4"><name><surname>Chiarelli</surname>
<given-names>Nicola</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>chiarell@med.unibs.it</email>
</contrib>
<contrib contrib-type="author" id="A5"><name><surname>Quinzani</surname>
<given-names>Stefano</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>stefano.quinzani@med.unibs.it</email>
</contrib>
<contrib contrib-type="author" id="A6"><name><surname>Traversa</surname>
<given-names>Michele</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>traversa@med.unibs.it</email>
</contrib>
<contrib contrib-type="author" id="A7"><name><surname>Zoppi</surname>
<given-names>Nicoletta</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>zoppi@med.unibs.it</email>
</contrib>
<contrib contrib-type="author" id="A8"><name><surname>Vascellaro</surname>
<given-names>Annalisa</given-names>
</name>
<xref ref-type="aff" rid="I2">2</xref>
<email>annalisavascellaro@hotmail.it</email>
</contrib>
<contrib contrib-type="author" id="A9"><name><surname>Wischmeijer</surname>
<given-names>Anita</given-names>
</name>
<xref ref-type="aff" rid="I3">3</xref>
<xref ref-type="aff" rid="I4">4</xref>
<email>anita.wischmeijer@unibo.it</email>
</contrib>
<contrib contrib-type="author" id="A10"><name><surname>Manfredini</surname>
<given-names>Emanuela</given-names>
</name>
<xref ref-type="aff" rid="I5">5</xref>
<email>Emanuela.Manfredini@OspedaleNiguarda.it</email>
</contrib>
<contrib contrib-type="author" id="A11"><name><surname>Garavelli</surname>
<given-names>Livia</given-names>
</name>
<xref ref-type="aff" rid="I3">3</xref>
<email>livia.garavelli@asmn.re.it</email>
</contrib>
<contrib contrib-type="author" id="A12"><name><surname>Calzavara-Pinton</surname>
<given-names>Piergiacomo</given-names>
</name>
<xref ref-type="aff" rid="I2">2</xref>
<email>calzavar@med.unibs.it</email>
</contrib>
<contrib contrib-type="author" corresp="yes" id="A13"><name><surname>Colombi</surname>
<given-names>Marina</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>colombi@med.unibs.it</email>
</contrib>
</contrib-group>
<aff id="I1"><label>1</label>
Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy</aff>
<aff id="I2"><label>2</label>
Department of Dermatology, University Hospital Spedali Civili, Brescia, Italy</aff>
<aff id="I3"><label>3</label>
Clinical Genetics Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S. Maria Nuova, Reggio Emilia, Italy</aff>
<aff id="I4"><label>4</label>
Department of Medical Genetics, Policlinico Sant’Orsola-Malpighi, University of Bologna, Bologna, Italy</aff>
<aff id="I5"><label>5</label>
Dipartimento Materno Infantile, Ospedale Niguarda Ca’ Granda, Milan, Italy</aff>
<pub-date pub-type="collection"><year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>12</day>
<month>4</month>
<year>2013</year>
</pub-date>
<volume>8</volume>
<fpage>58</fpage>
<lpage>58</lpage>
<history><date date-type="received"><day>4</day>
<month>2</month>
<year>2013</year>
</date>
<date date-type="accepted"><day>29</day>
<month>3</month>
<year>2013</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2013 Ritelli et al.; licensee BioMed Central Ltd.</copyright-statement>
<copyright-year>2013</copyright-year>
<copyright-holder>Ritelli et al.; licensee BioMed Central Ltd.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.0"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri xlink:href="http://www.ojrd.com/content/8/1/58"></self-uri>
<abstract><sec><title>Background</title>
<p>Classic Ehlers–Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect.</p>
</sec>
<sec><title>Methods</title>
<p>This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the <italic>COL5A1</italic>
gene and, if no mutation was detected, <italic>COL5A2</italic>
analysis. In the negative patients the presence of large genomic rearrangements in <italic>COL5A1</italic>
was investigated using MLPA, and positive results were confirmed via SNP-array analysis.</p>
</sec>
<sec><title>Results</title>
<p>We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands, <italic>COL5A1</italic>
or <italic>COL5A2</italic>
mutations were detected. Twenty-one mutations were in the <italic>COL5A1</italic>
gene, 18 of which were novel (2 recurrent). Of these, 16 mutations led to nonsense-mediated mRNA decay (NMD) and to COLLV haploinsufficiency and 5 mutations were structural. Two novel <italic>COL5A2</italic>
splice mutations were detected in patients with the most severe phenotypes. The known p. (Arg312Cys) mutation in the <italic>COL1A1</italic>
gene was identified in one patient with vascular-like cEDS.</p>
</sec>
<sec><title>Conclusions</title>
<p>Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical diagnosis in the large majority of the patients. The borderline patients for whom these criteria fail can be diagnosed when minor signs of connective tissue diseases and family history are present and when genetic testing reveals a defect in COLLV. Our data also confirm that <italic>COL5A1</italic>
and <italic>COL5A2</italic>
are the major, if not the only, genes involved in cEDS.</p>
</sec>
</abstract>
<kwd-group><kwd>Classic Ehlers–Danlos syndrome</kwd>
<kwd><italic>COL5A1</italic>
</kwd>
<kwd><italic>COL5A2</italic>
</kwd>
<kwd><italic>COL1A1</italic>
</kwd>
<kwd>MLPA</kwd>
<kwd>Diagnostic flowchart</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Italie</li>
</country>
<region><li>Lombardie</li>
</region>
<settlement><li>Milan</li>
</settlement>
</list>
<tree><country name="Italie"><noRegion><name sortKey="Ritelli, Marco" sort="Ritelli, Marco" uniqKey="Ritelli M" first="Marco" last="Ritelli">Marco Ritelli</name>
</noRegion>
<name sortKey="Calzavara Pinton, Piergiacomo" sort="Calzavara Pinton, Piergiacomo" uniqKey="Calzavara Pinton P" first="Piergiacomo" last="Calzavara-Pinton">Piergiacomo Calzavara-Pinton</name>
<name sortKey="Chiarelli, Nicola" sort="Chiarelli, Nicola" uniqKey="Chiarelli N" first="Nicola" last="Chiarelli">Nicola Chiarelli</name>
<name sortKey="Colombi, Marina" sort="Colombi, Marina" uniqKey="Colombi M" first="Marina" last="Colombi">Marina Colombi</name>
<name sortKey="Dordoni, Chiara" sort="Dordoni, Chiara" uniqKey="Dordoni C" first="Chiara" last="Dordoni">Chiara Dordoni</name>
<name sortKey="Garavelli, Livia" sort="Garavelli, Livia" uniqKey="Garavelli L" first="Livia" last="Garavelli">Livia Garavelli</name>
<name sortKey="Manfredini, Emanuela" sort="Manfredini, Emanuela" uniqKey="Manfredini E" first="Emanuela" last="Manfredini">Emanuela Manfredini</name>
<name sortKey="Quinzani, Stefano" sort="Quinzani, Stefano" uniqKey="Quinzani S" first="Stefano" last="Quinzani">Stefano Quinzani</name>
<name sortKey="Traversa, Michele" sort="Traversa, Michele" uniqKey="Traversa M" first="Michele" last="Traversa">Michele Traversa</name>
<name sortKey="Vascellaro, Annalisa" sort="Vascellaro, Annalisa" uniqKey="Vascellaro A" first="Annalisa" last="Vascellaro">Annalisa Vascellaro</name>
<name sortKey="Venturini, Marina" sort="Venturini, Marina" uniqKey="Venturini M" first="Marina" last="Venturini">Marina Venturini</name>
<name sortKey="Wischmeijer, Anita" sort="Wischmeijer, Anita" uniqKey="Wischmeijer A" first="Anita" last="Wischmeijer">Anita Wischmeijer</name>
<name sortKey="Wischmeijer, Anita" sort="Wischmeijer, Anita" uniqKey="Wischmeijer A" first="Anita" last="Wischmeijer">Anita Wischmeijer</name>
<name sortKey="Zoppi, Nicoletta" sort="Zoppi, Nicoletta" uniqKey="Zoppi N" first="Nicoletta" last="Zoppi">Nicoletta Zoppi</name>
</country>
</tree>
</affiliations>
</record>
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