Abstract
Neurofibromatosis type I (NF1) microdeletion syndrome, which is present in 4–11% of NF1 patients, is associated with a severe phenotype as it is caused by the deletion of NF1 and other genes in the 17q11.2 region. The variable expressivity of the disease makes it challenging to establish genotype–phenotype correlations, which also affects prognosis and counselling. We here describe a 3-year-old NF1 patient with an atypical deletion and a complex phenotype. The patient showed overgrowth, café au lait spots, inguinal freckling, and neurological abnormalities. The extent of the deletion was determined by means of array comparative genomic hybridisation, and its breakpoints were isolated by means of long-range polymerase chain reaction. Sequence analysis of the deletion junction fragment revealed the occurrence of an Alu-mediated recombination that led to the generation of a chimeric gene consisting of three exons of RNF135 and eleven exons of SUZ12. Interestingly, the deletion shares a common RNF135-centred region with another deletion described in a non-NF1 patient with overgrowth. In comparison with the normal RNF135 allele, the chimeric transcript was 350-fold over-expressed in peripheral blood, and the ADAP2 gene located upstream of RNF135 was also up-regulated. In line with this, the deletion causes the loss of a chromatin TD boundary, which entails the aberrant adoption of distal cis-acting regulatory elements. These findings suggest that RNF135 haploinsufficiency is related to overgrowth in patients with NF1 microdeletion syndrome and, for the first time, strongly indicate a position effect that warrants further genotype–phenotype correlation studies to investigate the possible existence of previously unknown pathogenic mechanisms.
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References
Bengesser K, Cooper DN, Steinmann K et al (2010) A novel third type of recurrent NF1 microdeletion mediated by nonallelic homologous recombination between LRRC37B-containing low-copy repeats in 17q11.2. Hum Mutat 31:742–751. doi:10.1002/humu.21254
Bengesser K, Vogt J, Mussotter T et al (2014) Analysis of crossover breakpoints yields new insights into the nature of the gene conversion events associated with large NF1 deletions mediated by nonallelic homologous recombination. Hum Mutat 35:215–226. doi:10.1002/humu.22473
Chen M, Licon K, Otsuka R et al (2013) Decoupling epigenetic and genetic effects through systematic analysis of gene position. Cell Rep 3:128–137. doi:10.1016/j.celrep.2012.12.003
Ciferri C, Lander GC, Maiolica A et al (2012) Molecular architecture of human polycomb repressive complex 2. Elife 2012:1–22. doi:10.7554/eLife.00005
De Raedt T, Brems H, Wolkenstein P et al (2003) Elevated risk for MPNST in NF1 microdeletion patients. Am J Hum Genet 72:1288–1292. doi:10.1086/374821
De Raedt T, Beert E, Pasmant E et al (2014) PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514:247–251. doi:10.1038/nature13561
Depienne C, Nava C, Keren B et al (2017) Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU. Hum Genet 136:463–479. doi:10.1007/s00439-017-1772-0
Douglas J, Cilliers D, Coleman K et al (2007) Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth. Nat Genet 39:963–965. doi:10.1038/ng2083
Gervasini C, Venturin M, Orzan F et al (2005) Uncommon Alu-mediated NF1 microdeletion with a breakpoint inside the NF1 gene. Genomics 85:273–279. doi:10.1016/j.ygeno.2004.10.014
Giorgio E, Robyr D, Spielmann M et al (2014) A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD). Hum Mol Genet 24:3143–3154. doi:10.1093/hmg/ddv065
Ibn-Salem J, Köhler S, Love MI et al (2014) Deletions of chromosomal regulatory boundaries are associated with congenital disease. Genome Biol 15:423. doi:10.1186/s13059-014-0423-1
Imagawa E, Higashimoto K, Sakai Y et al (2017) Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. Hum Mutat. doi:10.1002/humu.23200
Jelena B, Christina L, Eric V, Fabiola QR (2014) Phenotypic variability in Waardenburg syndrome resulting from a 22q12.3-q13.1 microdeletion involving SOX10. Am J Med Genet Part A 164:1512–1519. doi:10.1002/ajmg.a.36446
Kehrer-Sawatzki H, Tinschert SJDJ (2003) Heterogeneity of breakpoints in non-LCR-mediated large constitutional deletions of the 17q11.2 NF1 tumour suppressor region. J Med Genet. doi:10.1113/JP272283.This
Kehrer-Sawatzki H, Schmid E, Fünsterer C et al (2008) Absence of cutaneous neurofibromas in an NF1 patient with an atypical deletion partially overlapping the common 1.4 Mb microdeleted region. Am J Med Genet Part A 146:691–699. doi:10.1002/ajmg.a.32045
Kehrer-Sawatzki H, Mautner V-F, Cooper DN (2017) Emerging genotype–phenotype relationships in patients with large NF1 deletions. Hum Genet. doi:10.1007/s00439-017-1766-y
Kim Songmi, Cho Chun-Sung, Kyudong Han JL (2016) Structural variation of Alu element and human disease songmi. Genomics and Infomratics 14:70–77. doi:10.5808/GI.2016.14.3.70
Kluwe L, Siebert R, Gesk S et al (2004) Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat 23:111–116. doi:10.1002/humu.10299
Lammert M, Friedman JM, Kluwe L, Mautner VF (2017) Prevalence of neurofibromatosis 1 in german children at elementary school enrollment. Arch Dermatol 141:71–74
Lopez-Correa C, Brems H, La C et al (2000) Unequal meiotic crossover: a frequent cause of NF1 microdeletions. Am J Hum Genet 66:1969–1974
Mantripragada KK, Thuresson A-C, Piotrowski A et al (2006) Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH. J Med Genet 43:28–38. doi:10.1136/jmg.2005.033795
Martin I, Andres CR, Védrine S et al (2009) Effect of the oligodendrocyte myelin glycoprotein (OMgp) on the expansion and neuronal differentiation of rat neural stem cells. Brain Res 1284:22–30. doi:10.1016/j.brainres.2009.05.070
Mautner V-F, Kluwe L, Friedrich RE et al (2010) Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet 47:623–630. doi:10.1136/jmg.2009.075937
Messiaen L, Vogt J, Bengesser K et al (2011) Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum Mutat 32:213–219. doi:10.1002/humu.21418
Milot E, Fraser P, Grosveld F (1996) Position effects and genetic disease. Trends Genet 12:123–126
Mironova YA, Giger RJ (2013) Where no synapses go: gatekeepers of circuit remodeling and synaptic strength. Trends Neurosci 36:363–373. doi:10.1016/j.tins.2013.04.003
Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7:233–245. doi:10.1038/nrc2091
Ning X, Farschtschi S, Jones A et al (2016) Growth in neurofibromatosis 1 microdeletion patients. Clin Genet 89:351–354. doi:10.1111/cge.12632
Onea AS, Jazirehi AR (2016) CD19 chimeric antigen receptor (CD19 CAR)-redirected adoptive T-cell immunotherapy for the treatment of relapsed or refractory B-cell non-Hodgkin’s lymphomas. Am J Cancer Res 6:403–424
Pasmant E, de Saint-Trivier A, Laurendeau I et al (2008) Characterization of a 7.6-Mb germline deletion encompassing the NF1 locus and about a hundred genes in an NF1 contiguous gene syndrome patient. Eur J Hum Genet 16:1459–1466. doi:10.1038/ejhg.2008.134
Pasmant E, Sabbagh A, Spurlock G et al (2010) NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. doi:10.1002/humu.21271
Riva P, Corrado L, Natacci F et al (2000) NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes. Am J Hum Genet 66:100–109. doi:10.1086/302709
Rojnueangnit K, Xie J, Gomes A et al (2015) High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation. Hum Mutat 36:1052–1063. doi:10.1002/humu.22832
Ruggieri M, Polizzi A, Spalice A et al (2015) The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features. Clin Genet 87:401–410. doi:10.1111/cge.12498
Sabbagh A, Pasmant E, Imbard A et al (2013) NF1 molecular characterization and neurofibromatosis type i genotype-phenotype correlation: the french experience. Hum Mutat 34:1510–1518. doi:10.1002/humu.22392
Steinmann K, Kluwe L, Cooper DN et al (2008) Copy number variations in the NF1 gene region are infrequent and do not predispose to recurrent type-1 deletions. Eur J Hum Genet 16:572–580. doi:10.1038/sj.ejhg.5202002
Szudek J, Birch P, Friedman JM (2000) Growth in North American white children with neurofibromatosis 1 (NF1). J Med Genet 37:933–938
Upadhyaya M, Huson SM, Davies M et al (2007) An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c. 2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet 80(1):140–151
Uusitalo E, Leppävirta J, Koffert A et al (2015) Incidence and mortality of neurofibromatosis: a total population study in Finland. J Investig Dermatol 135(3):904–906. doi:10.1038/jid.2014.465
Venturin M, Gervasini C, Orzan F et al (2004) Evidence for non-homologous end joining and non-allelic homologous recombination in atypical NF1 microdeletions. Hum Genet 115:69–80. doi:10.1007/s00439-004-1101-2
Venturin M, Bentivegna A, Moroni R et al (2005) Evidence by expression analysis of candidate genes for congenital heart defects in the NF1 microdeletion interval. Ann Hum Genet 69:508–516. doi:10.1111/j.1529-8817.2005.00203.x
Venturin M, Carra S, Gaudenzi G et al (2014) ADAP2 in heart development: a candidate gene for the occurrence of cardiovascular malformations in NF1 microdeletion syndrome. J Med Genet 51:436–443. doi:10.1136/jmedgenet-2013-102240
Vogt J, Mussotter T, Bengesser K et al (2012) Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder. Hum Mutat 33:1599–1609. doi:10.1002/humu.22171
Vogt J, Bengesser K, Claes KBM et al (2014) SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints. Genome Biol 15(6):R80. doi:10.1186/gb-2014-15-6-r80
Wang X, Charng W-L, Chen C-A et al (2017) Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations. Nat Genet 49:613–617. doi:10.1038/ng.3815
Weckselblatt B, Rudd MK (2015) Human structural variation: mechanisms of chromosome rearrangements. Trends Genet 31:587–599. doi:10.1016/j.tig.2015.05.010
Weise A, Mrasek K, Klein E et al (2012) Microdeletion and microduplication syndromes. J Histochem Cytochem 60:346–358. doi:10.1369/0022155412440001
Zhou H, Mak PY, Mu H et al (2017) Combined inhibition of β-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo. Leukemia. doi:10.1038/leu.2017.87
Zuccotti P, Cartelli D, Stroppi M et al (2012) Centaurin-alpha2 interacts with beta-tubulin and stabilizes microtubules. PLoS One. doi:10.1371/journal.pone.0052867
Acknowledgements
The authors would like to thank Professor Cristina Battaglia (University of Milan) for kindly providing the control RNA samples and Dr. Marica Eoli (Carlo Besta Neorological Institute, Milan) for contributing to the clinical discussion.
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This study was supported by grants from the Italian Ministry of Health (RF-INN-2008-1204836) to ME and PR, the Telethon Foundation (GGP14074) to EB, and CARIPLO (Project 2014-0972) to FR.
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Ferrari, L., Scuvera, G., Tucci, A. et al. Identification of an atypical microdeletion generating the RNF135-SUZ12 chimeric gene and causing a position effect in an NF1 patient with overgrowth. Hum Genet 136, 1329–1339 (2017). https://doi.org/10.1007/s00439-017-1832-5
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DOI: https://doi.org/10.1007/s00439-017-1832-5