The Italian AICE-Genetics hemophilia a database: Results and correlation with clinical phenotype

Maurizio Margaglione, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Elena Santagostino, Giuseppe Tagariello, Anna Rita Tagliaferri, Ezio Zanon, Maria Patrizia Bicocchi, Giuseppe Castaldo, Flora Peyvandi, Rosa Santacroce, Francesca Torricelli, Elvira Grandone, Pier Mannuccio Mannucci, L. Contino, A. Accorsi, A. Scaraggi, N. Ciavarella, G. RodorigoR. Targhetta, G. Tagariello, D. Belvini, R. Salviato, R. Musso, G. Muleo, C. Biasoli, V. Rossi, S. Testa, G. L. Scapoli, D. Vincenti, M. Morfini, A. C. Molinari, M. P. Bicocchi, M. Girotto, G. Mariani, C. Ciabatta, M. T. Carloni, P. M. Mannucci, E. Santagostino, F. Peyvandi, F. Baudo, M. Marietta, C. Perricone, M. Schiavulli, A. Rocino, G. Di Minno, A. Coppola, M. Berrettini, E. Zanon, G. Mancuso, S. Siragusa, A. Tagliaferri, F. Rivolta, G. Gamba, A. Iorio, A. Dragani, M. C. Arbasi, A. Mancino, V. Trapani Lombardo, M. D'Incà, G. De Rossi, R. Landolfi, G. Mazzucconi, G. Piseddu, L. Perugini, M. Messina, G. Tamponi, P. Schinco, G. Rossetti, G. Barillari, A. Catalano, G. Feola, G. Gandini, G. Castaman, S. Giacomelli, R. Ghiotto

Research output: Contribution to journalArticle

Abstract

Background: The high mutational heterogeneity of hemophilia A is a challenge for the provision of genetic services.We plan to identify the mutation in patients with hemophilia A in order to create a confidential national database of mutations for the optimization of genetic services in Italy. Design and Methods: The factor VIII gene (F8) was analyzed in 1296 unrelated patients with hemophilia A using screening methods for intron 22 and 1 inversions and rare mutations (denaturing high performance liquid chromatography, conformation sensitive gel electrophoresis) and/or direct sequencing. Results: F8 mutations were identified in 874 (89%), 146 (89%), and 133 (94%) families with severe, moderate, or mild hemophilia A, respectively. Mutations predicting a null allele were responsible for 80%, 15%, and less than 1% of cases of severe, moderate, or mild hemophilia A, respectively. About 40% of missense and nonsense mutations occurred at a CpG site, arginines being most frequently affected. Of the small deletions or insertions, 29% occurred at one of two stretches of adenines, codons 1191-1194 (8As) and 1439-1441 (9As). Overall, these "hotspots" accounted for 31% of the point mutations in the patients with hemophilia A. Inhibitors developed in 22% of the patients with severe hemophilia A, 8% of those with moderate disease and in 4% of patients with mild hemophilia A. Patients who had severe hemophilia A and mutations predicting a null allele developed inhibitors more frequently (22 to 67%) than patients with missense mutations (5%). Conclusions: We report a wide spectrum of mutations in a large national database. The type of mutation was a strong predictor of the clinical phenotype. This database is expected to considerably improve the genetic counselling and medical care of families with hemophilia A in Italy.

Original languageEnglish
Pages (from-to)722-728
Number of pages7
JournalHaematologica
Volume93
Issue number5
DOIs
Publication statusPublished - May 2008

Fingerprint

Hemophilia A
Databases
Phenotype
Mutation
Genetic Services
Missense Mutation
Italy
Alleles
Nonsense Codon
Genetic Counseling
Factor VIII
Adenine
Point Mutation
Codon
Introns
Arginine
Electrophoresis
Gels
High Pressure Liquid Chromatography

Keywords

  • F8 gene
  • Hemophilia A
  • Hotspots
  • Mutations
  • Phenotype

ASJC Scopus subject areas

  • Hematology

Cite this

Margaglione, M., Castaman, G., Morfini, M., Rocino, A., Santagostino, E., Tagariello, G., ... Ghiotto, R. (2008). The Italian AICE-Genetics hemophilia a database: Results and correlation with clinical phenotype. Haematologica, 93(5), 722-728. https://doi.org/10.3324/haematol.12427

The Italian AICE-Genetics hemophilia a database : Results and correlation with clinical phenotype. / Margaglione, Maurizio; Castaman, Giancarlo; Morfini, Massimo; Rocino, Angiola; Santagostino, Elena; Tagariello, Giuseppe; Tagliaferri, Anna Rita; Zanon, Ezio; Bicocchi, Maria Patrizia; Castaldo, Giuseppe; Peyvandi, Flora; Santacroce, Rosa; Torricelli, Francesca; Grandone, Elvira; Mannucci, Pier Mannuccio; Contino, L.; Accorsi, A.; Scaraggi, A.; Ciavarella, N.; Rodorigo, G.; Targhetta, R.; Tagariello, G.; Belvini, D.; Salviato, R.; Musso, R.; Muleo, G.; Biasoli, C.; Rossi, V.; Testa, S.; Scapoli, G. L.; Vincenti, D.; Morfini, M.; Molinari, A. C.; Bicocchi, M. P.; Girotto, M.; Mariani, G.; Ciabatta, C.; Carloni, M. T.; Mannucci, P. M.; Santagostino, E.; Peyvandi, F.; Baudo, F.; Marietta, M.; Perricone, C.; Schiavulli, M.; Rocino, A.; Di Minno, G.; Coppola, A.; Berrettini, M.; Zanon, E.; Mancuso, G.; Siragusa, S.; Tagliaferri, A.; Rivolta, F.; Gamba, G.; Iorio, A.; Dragani, A.; Arbasi, M. C.; Mancino, A.; Trapani Lombardo, V.; D'Incà, M.; De Rossi, G.; Landolfi, R.; Mazzucconi, G.; Piseddu, G.; Perugini, L.; Messina, M.; Tamponi, G.; Schinco, P.; Rossetti, G.; Barillari, G.; Catalano, A.; Feola, G.; Gandini, G.; Castaman, G.; Giacomelli, S.; Ghiotto, R.

In: Haematologica, Vol. 93, No. 5, 05.2008, p. 722-728.

Research output: Contribution to journalArticle

Margaglione, M, Castaman, G, Morfini, M, Rocino, A, Santagostino, E, Tagariello, G, Tagliaferri, AR, Zanon, E, Bicocchi, MP, Castaldo, G, Peyvandi, F, Santacroce, R, Torricelli, F, Grandone, E, Mannucci, PM, Contino, L, Accorsi, A, Scaraggi, A, Ciavarella, N, Rodorigo, G, Targhetta, R, Tagariello, G, Belvini, D, Salviato, R, Musso, R, Muleo, G, Biasoli, C, Rossi, V, Testa, S, Scapoli, GL, Vincenti, D, Morfini, M, Molinari, AC, Bicocchi, MP, Girotto, M, Mariani, G, Ciabatta, C, Carloni, MT, Mannucci, PM, Santagostino, E, Peyvandi, F, Baudo, F, Marietta, M, Perricone, C, Schiavulli, M, Rocino, A, Di Minno, G, Coppola, A, Berrettini, M, Zanon, E, Mancuso, G, Siragusa, S, Tagliaferri, A, Rivolta, F, Gamba, G, Iorio, A, Dragani, A, Arbasi, MC, Mancino, A, Trapani Lombardo, V, D'Incà, M, De Rossi, G, Landolfi, R, Mazzucconi, G, Piseddu, G, Perugini, L, Messina, M, Tamponi, G, Schinco, P, Rossetti, G, Barillari, G, Catalano, A, Feola, G, Gandini, G, Castaman, G, Giacomelli, S & Ghiotto, R 2008, 'The Italian AICE-Genetics hemophilia a database: Results and correlation with clinical phenotype', Haematologica, vol. 93, no. 5, pp. 722-728. https://doi.org/10.3324/haematol.12427
Margaglione, Maurizio ; Castaman, Giancarlo ; Morfini, Massimo ; Rocino, Angiola ; Santagostino, Elena ; Tagariello, Giuseppe ; Tagliaferri, Anna Rita ; Zanon, Ezio ; Bicocchi, Maria Patrizia ; Castaldo, Giuseppe ; Peyvandi, Flora ; Santacroce, Rosa ; Torricelli, Francesca ; Grandone, Elvira ; Mannucci, Pier Mannuccio ; Contino, L. ; Accorsi, A. ; Scaraggi, A. ; Ciavarella, N. ; Rodorigo, G. ; Targhetta, R. ; Tagariello, G. ; Belvini, D. ; Salviato, R. ; Musso, R. ; Muleo, G. ; Biasoli, C. ; Rossi, V. ; Testa, S. ; Scapoli, G. L. ; Vincenti, D. ; Morfini, M. ; Molinari, A. C. ; Bicocchi, M. P. ; Girotto, M. ; Mariani, G. ; Ciabatta, C. ; Carloni, M. T. ; Mannucci, P. M. ; Santagostino, E. ; Peyvandi, F. ; Baudo, F. ; Marietta, M. ; Perricone, C. ; Schiavulli, M. ; Rocino, A. ; Di Minno, G. ; Coppola, A. ; Berrettini, M. ; Zanon, E. ; Mancuso, G. ; Siragusa, S. ; Tagliaferri, A. ; Rivolta, F. ; Gamba, G. ; Iorio, A. ; Dragani, A. ; Arbasi, M. C. ; Mancino, A. ; Trapani Lombardo, V. ; D'Incà, M. ; De Rossi, G. ; Landolfi, R. ; Mazzucconi, G. ; Piseddu, G. ; Perugini, L. ; Messina, M. ; Tamponi, G. ; Schinco, P. ; Rossetti, G. ; Barillari, G. ; Catalano, A. ; Feola, G. ; Gandini, G. ; Castaman, G. ; Giacomelli, S. ; Ghiotto, R. / The Italian AICE-Genetics hemophilia a database : Results and correlation with clinical phenotype. In: Haematologica. 2008 ; Vol. 93, No. 5. pp. 722-728.
@article{bb032889ffcb4bb9b05ddd6ffa1ff41d,
title = "The Italian AICE-Genetics hemophilia a database: Results and correlation with clinical phenotype",
abstract = "Background: The high mutational heterogeneity of hemophilia A is a challenge for the provision of genetic services.We plan to identify the mutation in patients with hemophilia A in order to create a confidential national database of mutations for the optimization of genetic services in Italy. Design and Methods: The factor VIII gene (F8) was analyzed in 1296 unrelated patients with hemophilia A using screening methods for intron 22 and 1 inversions and rare mutations (denaturing high performance liquid chromatography, conformation sensitive gel electrophoresis) and/or direct sequencing. Results: F8 mutations were identified in 874 (89{\%}), 146 (89{\%}), and 133 (94{\%}) families with severe, moderate, or mild hemophilia A, respectively. Mutations predicting a null allele were responsible for 80{\%}, 15{\%}, and less than 1{\%} of cases of severe, moderate, or mild hemophilia A, respectively. About 40{\%} of missense and nonsense mutations occurred at a CpG site, arginines being most frequently affected. Of the small deletions or insertions, 29{\%} occurred at one of two stretches of adenines, codons 1191-1194 (8As) and 1439-1441 (9As). Overall, these {"}hotspots{"} accounted for 31{\%} of the point mutations in the patients with hemophilia A. Inhibitors developed in 22{\%} of the patients with severe hemophilia A, 8{\%} of those with moderate disease and in 4{\%} of patients with mild hemophilia A. Patients who had severe hemophilia A and mutations predicting a null allele developed inhibitors more frequently (22 to 67{\%}) than patients with missense mutations (5{\%}). Conclusions: We report a wide spectrum of mutations in a large national database. The type of mutation was a strong predictor of the clinical phenotype. This database is expected to considerably improve the genetic counselling and medical care of families with hemophilia A in Italy.",
keywords = "F8 gene, Hemophilia A, Hotspots, Mutations, Phenotype",
author = "Maurizio Margaglione and Giancarlo Castaman and Massimo Morfini and Angiola Rocino and Elena Santagostino and Giuseppe Tagariello and Tagliaferri, {Anna Rita} and Ezio Zanon and Bicocchi, {Maria Patrizia} and Giuseppe Castaldo and Flora Peyvandi and Rosa Santacroce and Francesca Torricelli and Elvira Grandone and Mannucci, {Pier Mannuccio} and L. Contino and A. Accorsi and A. Scaraggi and N. Ciavarella and G. Rodorigo and R. Targhetta and G. Tagariello and D. Belvini and R. Salviato and R. Musso and G. Muleo and C. Biasoli and V. Rossi and S. Testa and Scapoli, {G. L.} and D. Vincenti and M. Morfini and Molinari, {A. C.} and Bicocchi, {M. P.} and M. Girotto and G. Mariani and C. Ciabatta and Carloni, {M. T.} and Mannucci, {P. M.} and E. Santagostino and F. Peyvandi and F. Baudo and M. Marietta and C. Perricone and M. Schiavulli and A. Rocino and {Di Minno}, G. and A. Coppola and M. Berrettini and E. Zanon and G. Mancuso and S. Siragusa and A. Tagliaferri and F. Rivolta and G. Gamba and A. Iorio and A. Dragani and Arbasi, {M. C.} and A. Mancino and {Trapani Lombardo}, V. and M. D'Inc{\`a} and {De Rossi}, G. and R. Landolfi and G. Mazzucconi and G. Piseddu and L. Perugini and M. Messina and G. Tamponi and P. Schinco and G. Rossetti and G. Barillari and A. Catalano and G. Feola and G. Gandini and G. Castaman and S. Giacomelli and R. Ghiotto",
year = "2008",
month = "5",
doi = "10.3324/haematol.12427",
language = "English",
volume = "93",
pages = "722--728",
journal = "Haematologica",
issn = "0390-6078",
publisher = "NLM (Medline)",
number = "5",

}

TY - JOUR

T1 - The Italian AICE-Genetics hemophilia a database

T2 - Results and correlation with clinical phenotype

AU - Margaglione, Maurizio

AU - Castaman, Giancarlo

AU - Morfini, Massimo

AU - Rocino, Angiola

AU - Santagostino, Elena

AU - Tagariello, Giuseppe

AU - Tagliaferri, Anna Rita

AU - Zanon, Ezio

AU - Bicocchi, Maria Patrizia

AU - Castaldo, Giuseppe

AU - Peyvandi, Flora

AU - Santacroce, Rosa

AU - Torricelli, Francesca

AU - Grandone, Elvira

AU - Mannucci, Pier Mannuccio

AU - Contino, L.

AU - Accorsi, A.

AU - Scaraggi, A.

AU - Ciavarella, N.

AU - Rodorigo, G.

AU - Targhetta, R.

AU - Tagariello, G.

AU - Belvini, D.

AU - Salviato, R.

AU - Musso, R.

AU - Muleo, G.

AU - Biasoli, C.

AU - Rossi, V.

AU - Testa, S.

AU - Scapoli, G. L.

AU - Vincenti, D.

AU - Morfini, M.

AU - Molinari, A. C.

AU - Bicocchi, M. P.

AU - Girotto, M.

AU - Mariani, G.

AU - Ciabatta, C.

AU - Carloni, M. T.

AU - Mannucci, P. M.

AU - Santagostino, E.

AU - Peyvandi, F.

AU - Baudo, F.

AU - Marietta, M.

AU - Perricone, C.

AU - Schiavulli, M.

AU - Rocino, A.

AU - Di Minno, G.

AU - Coppola, A.

AU - Berrettini, M.

AU - Zanon, E.

AU - Mancuso, G.

AU - Siragusa, S.

AU - Tagliaferri, A.

AU - Rivolta, F.

AU - Gamba, G.

AU - Iorio, A.

AU - Dragani, A.

AU - Arbasi, M. C.

AU - Mancino, A.

AU - Trapani Lombardo, V.

AU - D'Incà, M.

AU - De Rossi, G.

AU - Landolfi, R.

AU - Mazzucconi, G.

AU - Piseddu, G.

AU - Perugini, L.

AU - Messina, M.

AU - Tamponi, G.

AU - Schinco, P.

AU - Rossetti, G.

AU - Barillari, G.

AU - Catalano, A.

AU - Feola, G.

AU - Gandini, G.

AU - Castaman, G.

AU - Giacomelli, S.

AU - Ghiotto, R.

PY - 2008/5

Y1 - 2008/5

N2 - Background: The high mutational heterogeneity of hemophilia A is a challenge for the provision of genetic services.We plan to identify the mutation in patients with hemophilia A in order to create a confidential national database of mutations for the optimization of genetic services in Italy. Design and Methods: The factor VIII gene (F8) was analyzed in 1296 unrelated patients with hemophilia A using screening methods for intron 22 and 1 inversions and rare mutations (denaturing high performance liquid chromatography, conformation sensitive gel electrophoresis) and/or direct sequencing. Results: F8 mutations were identified in 874 (89%), 146 (89%), and 133 (94%) families with severe, moderate, or mild hemophilia A, respectively. Mutations predicting a null allele were responsible for 80%, 15%, and less than 1% of cases of severe, moderate, or mild hemophilia A, respectively. About 40% of missense and nonsense mutations occurred at a CpG site, arginines being most frequently affected. Of the small deletions or insertions, 29% occurred at one of two stretches of adenines, codons 1191-1194 (8As) and 1439-1441 (9As). Overall, these "hotspots" accounted for 31% of the point mutations in the patients with hemophilia A. Inhibitors developed in 22% of the patients with severe hemophilia A, 8% of those with moderate disease and in 4% of patients with mild hemophilia A. Patients who had severe hemophilia A and mutations predicting a null allele developed inhibitors more frequently (22 to 67%) than patients with missense mutations (5%). Conclusions: We report a wide spectrum of mutations in a large national database. The type of mutation was a strong predictor of the clinical phenotype. This database is expected to considerably improve the genetic counselling and medical care of families with hemophilia A in Italy.

AB - Background: The high mutational heterogeneity of hemophilia A is a challenge for the provision of genetic services.We plan to identify the mutation in patients with hemophilia A in order to create a confidential national database of mutations for the optimization of genetic services in Italy. Design and Methods: The factor VIII gene (F8) was analyzed in 1296 unrelated patients with hemophilia A using screening methods for intron 22 and 1 inversions and rare mutations (denaturing high performance liquid chromatography, conformation sensitive gel electrophoresis) and/or direct sequencing. Results: F8 mutations were identified in 874 (89%), 146 (89%), and 133 (94%) families with severe, moderate, or mild hemophilia A, respectively. Mutations predicting a null allele were responsible for 80%, 15%, and less than 1% of cases of severe, moderate, or mild hemophilia A, respectively. About 40% of missense and nonsense mutations occurred at a CpG site, arginines being most frequently affected. Of the small deletions or insertions, 29% occurred at one of two stretches of adenines, codons 1191-1194 (8As) and 1439-1441 (9As). Overall, these "hotspots" accounted for 31% of the point mutations in the patients with hemophilia A. Inhibitors developed in 22% of the patients with severe hemophilia A, 8% of those with moderate disease and in 4% of patients with mild hemophilia A. Patients who had severe hemophilia A and mutations predicting a null allele developed inhibitors more frequently (22 to 67%) than patients with missense mutations (5%). Conclusions: We report a wide spectrum of mutations in a large national database. The type of mutation was a strong predictor of the clinical phenotype. This database is expected to considerably improve the genetic counselling and medical care of families with hemophilia A in Italy.

KW - F8 gene

KW - Hemophilia A

KW - Hotspots

KW - Mutations

KW - Phenotype

UR - http://www.scopus.com/inward/record.url?scp=43449104265&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=43449104265&partnerID=8YFLogxK

U2 - 10.3324/haematol.12427

DO - 10.3324/haematol.12427

M3 - Article

C2 - 18387975

AN - SCOPUS:43449104265

VL - 93

SP - 722

EP - 728

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 5

ER -