126 novel mutations in Italian patients with neurofibromatosis type 1

被引:31
作者
Bianchessi, Donatella [1 ]
Morosini, Sara [1 ]
Saletti, Veronica [2 ]
Ibba, Maria Cristina [1 ]
Natacci, Federica [3 ]
Esposito, Silvia [2 ]
Cesaretti, Claudia [3 ]
Riva, Daria [2 ]
Finocchiaro, Gaetano [1 ]
Eoli, Marica [1 ]
机构
[1] IRCCS Fdn, C Besta Neurol Inst, Mol Neuro Oncol, Milan, Italy
[2] IRCCS Fdn, C Besta Neurol Inst, Dev Neurol, Milan, Italy
[3] IRCCS Fdn, Ca Grande Osped Maggiore Policlin, Med Genet, Milan, Italy
来源
MOLECULAR GENETICS & GENOMIC MEDICINE | 2015年 / 3卷 / 06期
关键词
Diagnostic criteria; mutation database; neurofibromatosis type 1 (NF1); novel mutations;
D O I
10.1002/mgg3.161
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation-dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA-based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.
引用
收藏
页码:513 / 525
页数:13
相关论文
共 54 条
  • [21] Eliminating barriers to personalized medicine Learning from neurofibromatosis type 1
    Gutmann, David H.
    [J]. NEUROLOGY, 2014, 83 (05) : 463 - 471
  • [22] Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 (NF1) gene
    Han, S
    Cooper, DN
    Upadhyaya, M
    [J]. HUMAN GENETICS, 2001, 109 (05) : 487 - 497
  • [23] Huson S. M., 2008, V16, P1, DOI 10.1159/000126500
  • [24] Clinical and genetic aspects of neurofibromatosis 1
    Jett, Kimberly
    Friedman, Jan M.
    [J]. GENETICS IN MEDICINE, 2010, 12 (01) : 1 - 11
  • [25] High frequency of mosaicism among patients with neurofibromatosis type 1 (NF1) with microdeletions caused by somatic recombination of the JJAZ1 gene
    Kehrer-Sawatzki, H
    Kluwe, L
    Sandig, C
    Kohn, M
    Wimmer, K
    Krammer, U
    Peyrl, A
    Jenne, DE
    Hansmann, I
    Mautner, VF
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 2004, 75 (03) : 410 - 423
  • [26] Identification of Large NF1 Duplications Reciprocal to NAHR-Mediated Type-1 NF1 Deletions
    Kehrer-Sawatzki, Hildegard
    Bengesser, Kathrin
    Callens, Tom
    Mikhail, Fady
    Fu, Chuanhua
    Hillmer, Morten
    Walker, Martha E.
    Saal, Howard M.
    Lacassie, Yves
    Cooper, David N.
    Messiaen, Ludwine
    [J]. HUMAN MUTATION, 2014, 35 (12) : 1469 - 1475
  • [27] Screening 500 unselected neuroflibromatosis 1 patients for deletions of the NF1 gene
    Kluwe, L
    Siebert, R
    Gesk, S
    Friedrich, RE
    Tinschert, S
    Kehrer-Sawatzki, H
    Mautner, VF
    [J]. HUMAN MUTATION, 2004, 23 (02) : 111 - 116
  • [28] Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions
    Mautner, V-F
    Kluwe, L.
    Friedrich, R. E.
    Roehl, A. C.
    Bammert, S.
    Hoegel, J.
    Spoerl, H.
    Cooper, D. N.
    Kehrer-Sawatzki, H.
    [J]. JOURNAL OF MEDICAL GENETICS, 2010, 47 (09) : 623 - 630
  • [29] Connective tissue dysplasia in five new patients with NF1 microdeletions:: further expansion of phenotype and review of the literature -: art. no. e8
    Mensink, KA
    Ketterling, RP
    Flynn, HC
    Knudson, RA
    Lindor, NM
    Heese, BA
    Spinner, RJ
    Babovic-Vuksanovic, D
    [J]. JOURNAL OF MEDICAL GENETICS, 2006, 43 (02)
  • [30] Messiaen LM, 2000, HUM MUTAT, V15, P541, DOI 10.1002/1098-1004(200006)15:6<541::AID-HUMU6>3.0.CO