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Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification

¹ IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy
² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
³ IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy
⁴ Department of Dermatology-Venereology and Plastic and Reconstructive Surgery, University of Rome "La Sapienza", Rome, Italy
⁵ IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, Rome, Italy
⁶ Department of Experimental Medicine and Pathology, University of Rome "La Sapienza", Rome, Italy

Correspondence to:
Professor Bruno Dallapiccola, Dipartimento di Medicina Sperimentale e Patologia, Universitè degli Studi di Roma "La Sapienza", Viale Regina Margherita 261–00198 Rome, Italy; dallapiccola{at}css-mendel.it]

To estimate the contribution of single and multi-exon NF1 gene copy-number changes to the NF1 mutation spectrum, we analysed a series of 201 Italian patients with neurofibromatosis type 1 (NF1). Of these, 138 had previously been found, using denaturing high-performance liquid chromatography or protein truncation test, to be heterozygous for intragenic NF1 point mutations/deletions/insertions, and were excluded from this analysis. The remaining 63 patients were analysed using multiplex ligation-dependent probe amplification (MLPA), which allows detection of deletions or duplications encompassing 1 NF1 exons, as well as entire gene deletions. MLPA results were validated using real-time quantitative PCR (qPCR) or fluorescent in situ hybridisation. MLPA screening followed by real-time qPCR detected a total of 23 deletions. Of these deletions, six were single exon, eight were multi-exon, and nine were of the entire NF1 gene. In our series, deletions encompassing 1 NF1 exons accounted for 7% (14/201) of the NF1 gene mutation spectrum, suggesting that screening for these should now be systematically included in genetic testing of patients with NF1.

Abbreviations: CSRD, cysteine-serine rich domain; DHPLC, denaturing high-performance liquid chromatography; FISH, fluorescence in situ hybridisation; GAP, GTPase-activating protein; MLPA, multiplex ligation-dependent probe amplification; NIH, National Institutes of Health; NF1, neurofibromatosis type 1; OMIM, Online Mendelian Inheritance in Man; PTT, protein truncation test; qPCR, quantitative PCR; SSCP, single-strand conformational polymorphism